Pharmaceutical compositions for NEK7 kinase inhibitors

Abstract

A pharmaceutical composition for a compound that is an inhibitor of NEK7 is provided. The compound is of formula (I) [Formula 1] The structure of JPEG2026524721000075.jpg4463, or a pharmaceutically acceptable salt or solvate thereof, and its modifications are as defined herein. This specification also provides methods of treatment comprising the pharmaceutical compositions described herein.

Description

[Technical Field]

[0001] cross reference This application claims the interests of U.S. Provisional Patent Application No. 63 / 512,188, filed on 6 July 2023, and U.S. Provisional Patent Application No. 63 / 657,018, filed on 6 June 2024, both of which are incorporated herein by reference in their entirety. [Background technology]

[0002] The NLRP3 inflammasome is a multi-protein complex containing NLRP3, ASC, and caspase-1. NEK7 is a member of the NIMA-associated kinase (NEK) family and acts as an NLRP3-binding protein to regulate its oligomerization and activation. [Overview of the project]

[0003] This specification includes formula (I)

[0004] [ka] A pharmaceutical composition is provided comprising a compound, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and at least one pharmaceutically acceptable excipient. During the ceremony, A is C6~C 10 Aryl, C3~C 10 They are cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which has one or more R 6 Then, it is replaced by an optional selection. X is either CH or N, Y is NH, R 1 H is H, R 2is C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl, or 5-6 member heteroaryl, each of which is optionally substituted with one further substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 member heterocyclyl, R 3 is H, R 4 is heteroaryl selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, each of which is optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclylalkyl, and C3-C8 halocycloalkyl, R 5 is H, each R 6 is independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl, or C1-C6 haloalkyl, wherein the pharmaceutical composition comprises up to 10 mg of formula (I).

[0005] One aspect of the disclosure is formula (I)

[0006]

Chemical formula

[0007] In some embodiments, pharmaceutically acceptable excipients include sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, or magnesium stearate, or a combination of two or more of these.

[0008] One aspect of this disclosure provides a method for treating an NLRP3-mediated disease or disorder in a subject requiring treatment of such disease or disorder, the method comprising administering to the subject a therapeutically effective dose of a pharmaceutical composition disclosed herein.

[0009] In some embodiments, the NLRP3-mediated disease or disorder is myelodysplastic syndrome.

[0010] In some embodiments, the compound is of formula (Ia)

[0011] [ka] A compound of, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, During the ceremony, R 2a This is a C3-C4 cycloalkyl that is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. R 4a isoxazolyl is optionally substituted with one or more substituents selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, or C3-C8 haloalkylcycloalkyl.

[0012] In some embodiments, the compound of formula (I) is one of those listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0013] In some embodiments, the compound of formula (I) is

[0014] [ka]

[0015] [ka] or selected from pharmaceutically acceptable salts or solvates thereof.

[0016] In some embodiments, the compound of formula (I) is compound 10 in Table 1.

[0017] In some embodiments, the amount of compound (I) in the pharmaceutical composition is about 4 mg.

[0018] In some embodiments, the amount of compound (I) in the pharmaceutical composition is about 5 mg.

[0019] In some embodiments, the amount of compound (I) in the pharmaceutical composition is about 2 mg.

[0020] In some embodiments, the amount of compound (I) in the pharmaceutical composition is about 0.5 mg.

[0021] In some embodiments, the pharmaceutical composition is a tablet.

[0022] In some embodiments, the tablet is a film-coated immediate-release tablet.

[0023] In some embodiments, the tablets are coated with Opadry II.

[0024] In some embodiments, the tablets have a diameter of approximately 7 mm.

[0025] In some embodiments, pharmaceutically acceptable excipients include sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, magnesium stearate, or a combination of two or more of these.

[0026] In some embodiments, pharmaceutically acceptable excipients include at least three components selected from the group consisting of sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, and magnesium stearate.

[0027] In some embodiments, pharmaceutically acceptable excipients include at least four components selected from the group consisting of sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, and magnesium stearate.

[0028] In some embodiments, pharmaceutically acceptable excipients include at least five components selected from the group consisting of sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, and magnesium stearate.

[0029] In some embodiments, pharmaceutically acceptable excipients include sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, and magnesium stearate.

[0030] In some embodiments, the amount of sodium lauryl sulfate is about 0.01% w / w to about 0.1% w / w.

[0031] In some embodiments, the amount of partially gelatinized corn starch is approximately 30% w / w to approximately 50% w / w.

[0032] In some embodiments, the amount of microcrystalline cellulose is approximately 30% w / w to approximately 50% w / w.

[0033] In some embodiments, the amount of sodium starch glycolate is about 1% w / w to about 5% w / w.

[0034] In some embodiments, the amount of hydroxypropylcellulose LF is about 1% w / w to about 5% w / w.

[0035] In some embodiments, the amount of colloidal silicon dioxide is approximately 0.5% w / w to approximately 5% w / w.

[0036] In some embodiments, the amount of magnesium stearate is approximately 0.5% w / w to approximately 5% w / w.

[0037] In some embodiments, the amount of sodium lauryl sulfate is about 0.01% w / w to about 0.1% w / w, the amount of partially gelatinized corn starch is about 43% w / w to about 44% w / w, the amount of microcrystalline cellulose is about 44% w / w to about 48% w / w, the amount of sodium starch glycolate is about 3% w / w to about 4% w / w, the amount of hydroxypropyl cellulose LF is about 2% w / w to about 3% w / w, the amount of colloidal silicon dioxide is about 1% w / w to about 1.5% w / w, and the amount of magnesium stearate is about 1% w / w to about 1.5% w / w.

[0038] In some embodiments, sodium lauryl sulfate is Kolliphore SLS fine, partially gelatinized corn starch is Starch 1500, microcrystalline cellulose is Avicel PH 101, sodium starch glycolate is Type A, hydroxypropyl cellulose LF is Klucel HPC LF, and colloidal silicon dioxide is Aerosil Pharma 200.

[0039] In one embodiment, the Disclosure provides a method for treating an NLRP3-mediated disease or disorder in a subject requiring treatment for such disease or disorder, the method comprising administering to the subject a therapeutically effective dose of a pharmaceutical composition disclosed herein.

[0040] In some embodiments, NLRP3-mediated diseases or disorders are myelodysplastic syndromes, inflammatory diseases or disorders, autoimmune diseases or disorders, cardiovascular diseases, neurodegenerative diseases or disorders, bacterial and / or viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, erythrocytosis, graft rejection, lung injury, respiratory diseases, ischemic conditions, or combinations thereof.

[0041] In some embodiments, the NLRP3-mediated disease or disorder is myelodysplastic syndrome, or an inflammatory disease or disorder.

[0042] In some embodiments, the NLRP3-mediated disease or disorder is myelodysplastic syndrome.

[0043] In some embodiments, myelodysplastic syndromes include myelodysplastic syndromes with multilineage dysplasia, myelodysplastic syndromes with single lineage dysplasia, myelodysplastic syndromes with ring sideroblasts, myelodysplastic syndromes with excess blasts, myelodysplastic syndromes with isolated deltas, or myelodysplastic syndromes that cannot be classified.

[0044] In some embodiments, the NLRP3-mediated disease or disorder is an inflammatory disease or disorder.

[0045] In some embodiments, the inflammatory disease or disorder is acute inflammatory pain.

[0046] In some embodiments, the pharmaceutical composition is administered daily.

[0047] In some embodiments, the pharmaceutical composition is administered daily for about 1 to 12 weeks.

[0048] In some embodiments, the pharmaceutical composition is administered daily for about 12 weeks or more.

[0049] In one embodiment, the present disclosure provides a method for treating myelodysplastic syndrome (MDS) in a subject requiring treatment for the condition, wherein the subject is given formula (I)

[0050] [ka] The process includes administering the compound, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. During the ceremony, A is C6~C 10 Aryl, C3~C 10 They are cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which has one or more R 6 Then, it is replaced by an optional selection. X is either CH or N, Y is NH, R 1 H is H, R 2 These are C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl, or 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. R 3 H is H, R 4It is a heteroaryl selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl. Each of these is optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclyl, and C3-C8 halocycloalkyl. R 5 H is H, Each R 6 These are independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl, or C1-C6 haloalkyl. Here, (i) The subjects are those who have symptomatic anemia, (ii) The subjects are refractory, intolerant of, or ineligible for treatment with erythroid stimulating agents (ESAs), and are selected on an optional basis, having discontinued previous ESA treatment at least two weeks prior to administration. (iii) The subjects have very low-risk MDS, low-risk MDS, or medium-risk MDS, (iv) The administration step involves orally administering the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to a subject. (v) The administration step involves administering the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to the subject on a daily basis, or (vi) A combination of two or more of (i) to (v).

[0051] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject daily.

[0052] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject daily for approximately 1 to 12 weeks.

[0053] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject daily for at least 12 weeks.

[0054] In some embodiments, administration involves orally administering a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to a subject.

[0055] In some embodiments, the dose of the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is approximately 0.5 mg to approximately 5 mg.

[0056] In some embodiments, formula (I)

[0057] [ka] The compound is the compound of formula (Ia), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. During the ceremony, R 2aThis is a C3-C4 cycloalkyl that is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. R 4a isoxazolyl is optionally substituted with one or more substituents selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, or C3-C8 haloalkylcycloalkyl.

[0058] In some embodiments, the compound of formula (I) is one of those listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0059] In some embodiments, the compound of formula (I) is compound 10 of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0060] In some embodiments, the compound of formula (I) is

[0061] [ka]

[0062] [ka] or selected from pharmaceutically acceptable salts or solvates thereof.

[0063] This specification provides a method for treating a disease or disorder in a subject requiring treatment of such disease or disorder, the method comprising administering to the subject a therapeutically effective dose of a pharmaceutical composition described herein. [Brief explanation of the drawing]

[0064] [Figure 1]The plasma concentration-time profiles resulting from the administration of 1 mg to 4 mg of compound 10 over two cycles of 5 days on and 2 days off are shown. Detailed description of the invention

[0065] The embodiments described herein generally relate to pharmaceutical compositions and methods for use, for example, as therapeutic or prophylactic agents for the treatment of inflammation and / or cancer.

[0066] definition Unless otherwise defined, all technical terms, notations, and other technical and scientific terms or terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art in the field relating to the claimed subject matter. In some cases, terms having a commonly understood meaning are defined herein for clarity and / or for ease of reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from the generally understood meaning in the art.

[0067] Throughout this application, various embodiments may be presented in scope form. It should be understood that the scope form is merely for convenience and brevity and should not be interpreted as an inflexible limitation to the scope of this disclosure. Therefore, a scope description should be considered to have all possible sub-scopes specifically disclosed, as well as the individual numbers within those scopes. For example, a scope description such as 1–6 should be considered to specifically disclose sub-scopes such as 1–3, 1–4, 1–5, 2–4, 2–6, 3–6, as well as the individual numbers within those scopes, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the scope.

[0068] When used in the specification and claims, the singular forms "a," "an," and "the" include multiple references unless the context explicitly indicates otherwise. For example, the term "a sample" includes multiple samples and mixtures thereof.

[0069] In this description, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the range described, and, where appropriate, fractions thereof (such as one-tenth and one-hundredth of an integer), unless otherwise indicated. Where used herein, the terms “about” and “approximately” mean ±5% or ±1% of the indicated range, value, or structure, unless otherwise indicated.

[0070] "Pharmaceutical composition" refers to formulations of the compounds of this disclosure and media generally accepted in the art for delivery of the compounds of this disclosure to mammals, such as humans. Such media include all pharmaceutically acceptable carriers, diluents, or excipients thereof.

[0071] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvants, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers.

[0072] "Amino" refers to the -NH2 radical.

[0073] "Carboxylate" or "carboxyl" refers to the -CO2H radical.

[0074] "Cyano" refers to the -CN radical.

[0075] "Hydroxy" or "hydroxyl" refers to the -OH radical.

[0076] "Nitro" refers to the -NO2 radical.

[0077] "Oxo" refers to an =O substituent.

[0078] "Thiol" refers to the -SH substituent.

[0079] "thioxo" refers to the =S substituent.

[0080] "Alkyl" refers to a saturated linear or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, which has 1 to 12 carbon atoms (C1 to C1). 12 A alkyl group has 1 to 8 carbon atoms (C1-C8 alkyl), or 1 to 6 carbon atoms (C1-C6 alkyl), or any value within these ranges, such as C4-C6 alkyl, and is bonded to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc. The number of carbon atoms mentioned relates to the carbon skeleton and carbon branching, but does not include carbon atoms belonging to any substituent. Unless otherwise specified herein, alkyl groups are optionally substituted.

[0081] "Alkenyl" refers to an unsaturated linear or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, which contains one or more carbon-carbon double bonds and 2 to 12 carbon atoms (C2-C2). 12Alkenyl groups have 2 to 8 carbon atoms (C2-C8 alkenyls), or 2 to 6 carbon atoms (C2-C6 alkenyls), or any value within these ranges, and are bonded to the rest of the molecule by single bonds, such as ethenyl, prop-1-enyl, but-1-enyl, penta-1-enyl, penta-1,4-dienyl, etc. The number of carbon atoms mentioned relates to the carbon skeleton and carbon branching, but does not include carbon atoms belonging to any substituent. Unless otherwise specified herein, alkenyl groups are optionally substituted.

[0082] "Alkynyl" refers to an unsaturated linear or branched hydrocarbon radical, which consists of 2 to 12 carbon atoms (C2 to C2). 12 Alkynyl groups have 2 to 9 carbon atoms (C2-C9 alkynyl), or 2 to 6 carbon atoms (C2-C6 alkynyl), or any value within these ranges, and have at least one carbon-carbon triple bond. Examples of alkynyl groups can be selected from the group consisting of ethynyl, propargyl, but-1-inyl, but-2-inyl, etc. The number of carbons mentioned relates to the carbon skeleton and carbon branching, but does not include carbon atoms belonging to any substituent. Unless otherwise specified herein, alkynyl groups are optionally substituted.

[0083] "alkoxy" is expressed in the formula -OR a This refers to the radical of the expression, where R is located in the formula. a This is an alkyl radical as defined above, which consists of 1 to 12 carbon atoms (C1 to C1). 12 It contains an alkoxy group, 1 to 8 carbon atoms (C1-C8 alkoxy), or 1 to 6 carbon atoms (C1-C6 alkoxy), or any value within these ranges. Unless otherwise specified herein, the alkoxy group may be optionally substituted.

[0084] "Aminyl" is derived from the formula -NR a R b This refers to the radical of the expression, where R is located in the formula. aRb and Rb are independently H or the C1-C6 alkyl groups defined above. a and R b If both are H, the "aminyl" group is the same as the "amino" group defined above. Unless otherwise specified, the C1-C6 alkyl portion of the aminyl group can be optionally substituted.

[0085] "Aminylalkylcycloalkyl" is defined by formula -R a R b NR c R d This refers to the radical of the expression, where R is located in the formula. a R is a cycloalkyl as defined herein, b It is a C1-C6 alkyl group, and R c is H or C1-C6 alkyl, and R d These are C1-C6 alkyl groups as defined above. Unless otherwise specified, the cycloalkyl portion and each C1-C6 alkyl portion of the aminylalkylcycloalkyl group can be optionally substituted.

[0086] An "aromatic ring" refers to a cyclic planar molecule or part of a molecule (i.e., a radical) having a ring of resonant bonds that exhibit increased stability compared to other bonding configurations with the same set of atoms. Generally, an aromatic ring contains a set of covalently bonded coplanar atoms and an even number of π electrons that are not multiples of 4 (e.g., alternating double and single bonds) (i.e., 4n + 2π electrons, where n = 0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridadinyl, and pyrimidonyl. Unless otherwise specified herein, "aromatic ring" includes all radicals that are optionally substituted.

[0087] "aryl" refers to a group of 6 to 18 carbon atoms, for example, 6 to 10 carbon atoms (C6~C6). 10This refers to a ring system radical comprising an aryl group and at least one carbocyclic aromatic ring. For the purposes of the embodiments of the present invention, the aryl radical may be a monocyclic, dicyclic, tricyclic, or tetracyclic ring system and may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluorantene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified herein, the aryl group may be optionally substituted.

[0088] "Cyanoalkyl" refers to an alkyl group containing at least one cyano substituent. The -CN substituent may be on a primary, secondary, or tertiary carbon. Unless otherwise specified herein, cyanoalkyl groups are optionally substituted.

[0089] A "carbocyclic" or "carbocycle" refers to a ring system, where each ring atom is carbon.

[0090] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic carbocyclic radical consisting only of carbon and hydrogen atoms. This can include fused or bridging ring systems and may contain 3 to 15 ring carbon atoms (C3-C). 15 Cycloalkyl), 3-10 ring carbon atoms (C3-C 10Monocyclic radicals have cycloalkyl groups, or 3 to 8 ring carbon atoms (C3-C8 cycloalkyl groups), or any value within these ranges, for example, 3 to 4 carbon atoms (C3-C4 cycloalkyl groups), and are saturated or partially unsaturated, and are bonded to the rest of the molecule by a single bond. Examples of monocyclic radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic radicals include adamantyl, norbornyl, dekalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, etc. Unless otherwise specified herein, cycloalkyl groups are optionally substituted.

[0091] "Alkylcycloalkyl (alkylcycloalkyl)" is represented by formula -R a R b It refers to the radical group, and in the formula, R a R is a cycloalkyl group, b is an alkyl group as defined above. Unless otherwise specified herein, alkylcycloalkyl groups are optionally substituted.

[0092] "Fused" refers to any ring structure described herein that is fused to another ring structure.

[0093] "Halo" refers to bromo, chloro, fluoro, or iodine.

[0094] "Haloalkyl" refers to an alkyl radical as defined above, which is substituted by one or more halo radicals as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specified herein, haloalkyls are optionally substituted.

[0095] "Halocycloalkyl" refers to a cycloalkyl radical as defined above, which is substituted by one or more halo radicals as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specified herein, halocycloalkyls are optionally substituted.

[0096] Haloalkylcycloalkyl is a compound of the formula -R a R b It refers to the radical group, and in the formula, R a R is a cycloalkyl group, b is a haloalkyl group as defined above. Unless otherwise specified herein, haloalkylcycloalkyl groups may be optionally substituted.

[0097] "Hydroxyalkyl" refers to an alkyl radical as defined above, which is substituted by one or more hydroxyl radicals. Hydroxyalkyl radicals are joined in the main chain via alkyl carbon atoms. Unless otherwise specified herein, hydroxyalkyl groups are optionally substituted.

[0098] A "heterocyclyl" refers to a 3- to 18-membered, e.g., 3- to 10-membered or 3- to 8-membered non-aromatic ring radical having 1 to 10 ring carbon atoms (e.g., 2 to 10) and 1 to 6 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless otherwise specified herein, heterocyclyl radicals are partially or fully saturated and are monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused ring systems, spirocyclic ring systems, and / or bridging ring systems. The nitrogen, carbon, and sulfur atoms in the heterocyclyl radical are optionally oxidized, and the nitrogen atom is optionally quaternized. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanil, thienyl[1,3]dithianil, decahydroisoquinolyl, furanolil, imidazolinil, imidazolidinil, isothiazolidinil, isoxazolidinil, morpholinil, octahydroindolyl, octahydroisoindolyl, hexahydro-1H-pyrrolizidine, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, oxazolidinil, oxylanil, piperidinil, piperadinil, 4-piperidonil, azetidinil, pyrrolidinil, pyrazolidinil, quinuclidinil, thiazolidinil, tetrahydrofuryl, trithianil, tetrahydropyranil, thiomorpholinil, thiamorpholinil, 1-oxo-thiomorpholinil, and 1,1-dioxo-thiomorpholinil. Unless otherwise specified herein, heterocyclyl groups are optionally substituted.

[0099] "Haloheterocyclylalkyl" is defined by formula -R a R b It refers to the radical group, and in the formula, R a R is an alkyl group, b is a haloheterocyclyl group as defined herein. Unless otherwise specified herein, haloheterocyclylalkyl groups are optionally substituted.

[0100] "heterocyclylalkyl" is defined by formula -R a R b It refers to the radical group, and in the formula, R a R is an alkyl group, b is a heterocyclyl group as defined herein. Unless otherwise specified herein, heterocyclylalkyl groups are optionally substituted.

[0101] A "heteroaryl" refers to a 5-18 membered, for example, 5-6 membered, cyclic radical containing 1-13 ring carbon atoms, 1-6 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. Heteroaryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic systems, including condensed or bridging ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, sinnolinil, dibenzofuranil, dibenzothiophenyl, furanil, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl This includes, but is not limited to, indolinyl, isoindolinyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetraazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, heteroaryl groups are optionally substituted.

[0102] Oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl are, respectively, as follows:

[0103] [ka] It refers to the structure, In the formula, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl are oxazolyl, isoxazolyl, The rest of the molecule is bonded to one of the carbon atoms in the ring of 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl by a covalent bond to one of the carbon atoms in the ring.

[0104] As used herein, the term “substituted” means any of the above groups (e.g., alkyl, alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminylalkyl, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclene, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and / or hydroxylalkyl) in which at least one hydrogen atom (e.g., one, two, three, or all hydrogen atoms) is replaced by bonding to a non-hydrogen substituent. Examples of non-hydrogen substituents include, but are not limited to, amino, carboxyl, cyano, hydroxyl, halo, nitro, oxo, thiol, thioxo, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and / or hydroxylalkyl substituents, each of which may also be optionally substituted with one or more of the above substituents.

[0105] In some specific embodiments, optional substitutions are independently halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C 10 The group is selected from aryls, 5-6 membered heteroaryls, C1-C6 alkoxys, and 3-8 membered heterocyclines.

[0106] "Effective amount" or "therapeutic effective amount" refers to an amount of the compound described herein that is sufficient to affect the intended use, including but not limited to the treatment of the disease as defined below.

[0107] As used herein, “treatment” or “treating” means an approach to obtain a beneficial or desired outcome with respect to a disease, disorder, or medical condition, including, but not limited to, therapeutic and / or prophylactic effects. A therapeutic benefit includes the elimination or improvement of the underlying disorder being treated. A therapeutic benefit may also be achieved by the elimination or improvement of one or more physiological symptoms associated with the underlying disorder, such that improvement is observed in the subject, even though the subject may still be suffering from the underlying disorder. A prophylactic effect includes delaying or eliminating the onset of a disease or illness, delaying or eliminating the onset of symptoms of a disease or illness, slowing, stopping, or reversing the progression of a disease or illness, or any combination thereof. In certain embodiments, for a prophylactic benefit, the composition is administered to a subject at risk of developing a particular disease, or to a subject reporting one or more physiological symptoms of the disease, even if a diagnosis of the disease has not been made.

[0108] The terms “co-administration” and “administered in combination with,” and their grammatical equivalents, as used herein, encompass the administration of two or more drugs to an animal, including humans, such that both drugs and / or their metabolites are present in the target simultaneously. Co-administration includes co-administration in separate compositions, administration in separate compositions at different times, or administration in a composition in which both drugs are present.

[0109] "Pharmacologically acceptable salts" include both acid addition salts and base addition salts.

[0110] A "pharmaceutically acceptable acid addition salt" refers to a salt that retains the biological efficacy of a free base and is therefore biologically acceptable or otherwise biologically suitable for administration to a subject. See, for general information, SMBerge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. A preferred pharmaceutically acceptable acid addition salt is one that is pharmacologically effective and suitable for contact with patient tissues without excessive toxicity, irritation, or allergic reactions.Inorganic acids, for example, but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids, for example, but not limited to acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonate, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid pharmaceutically acceptable acid addition salts formed with (a) glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucinic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid.

[0111] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effectiveness of a free acid and is biologically acceptable or otherwise biologically suitable for administration to a subject. See, for general information, SMBerge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. A preferred pharmaceutically acceptable base addition salt is one that is pharmacologically effective and suitable for contact with a patient's tissue without excessive toxicity, irritation, or allergic reactions. pharmaceutically acceptable base addition salts are prepared from the addition of an inorganic or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, benetamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0112] In some embodiments, pharmaceutically acceptable salts include quaternary ammonium salts such as quaternary amine alkyl halide salts (e.g., methyl bromide).

[0113] The terms “antagonist” and “inhibitor” are used interchangeably and refer to compounds that have the ability to inhibit the biological function of a target protein, whether by inhibiting the activity or expression of the NLRP3 inflammasome or NEK7 protein, or by inhibiting the association of the NLRP3 inflammasome-NEK7 protein. Thus, the terms “antagonist” and “inhibitors” are defined in the context of the biological role of the target protein. Preferred antagonists as used herein are compounds that specifically interact with (e.g., bind to) the target, but also inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway to which the target protein is a member. Preferred biological activities inhibited by antagonists are those related to tumor development, growth, or spread.

[0114] As used herein, the term “agonist” refers to a compound that has the ability to initiate or enhance the biological function of a target protein, whether or not it inhibits the activity or expression of the target protein. Therefore, the term “agonist” is defined in the context of the biological role of the target polypeptide. Preferred agonists as used herein include compounds that specifically interact with (e.g., bind to) the target, but also initiate or enhance the biological activity of the target polypeptide by interacting with other members of a signaling pathway to which the target polypeptide is a member.

[0115] "Subject" refers to mammals, such as humans. The methods described herein may be useful in both human therapeutic and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is a human.

[0116] The term "mammal" includes both humans and domesticated animals such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), as well as non-domesticated animals such as wild animals.

[0117] Certain embodiments also mean that they include in vivo metabolites of the disclosed compounds. Such products may arise, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily by enzymatic processes. Thus, embodiments include compounds produced by processes that involve administering the compounds of the disclosed to mammals for a period of time sufficient to produce their metabolites. Such products are typically identified by administering a detectable dose of the radiolabeled compound of the disclosed to animals such as rats, mice, guinea pigs, monkeys, or humans, which allows sufficient time for metabolism to occur and for the conversion products to be isolated from urine, blood, or other biological samples.

[0118] Crystallization often produces solvates of the compounds disclosed herein. As used herein, the term “solvate” refers to an aggregate comprising one or more compounds of the Disclosure together with one or more molecules of a solvent. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of the Disclosure may exist as hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the corresponding solvated forms. In some embodiments, the compounds of the Disclosure are true solvates, while in others, the compounds of the Disclosure are simply holding exogenous water or a mixture of water and some exogenous solvent.

[0119] A "stereoisomer" refers to a compound composed of the same atoms that are bonded together by the same bonds but have different three-dimensional structures, and these are not interchangeable. This disclosure intends to describe various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0120] The compounds of the present disclosure (i.e., compounds of formula (I)) or their pharmaceutically acceptable salts may contain one or more centers of geometric asymmetry, thus giving rise to stereoisomers such as enantiomers, diastereomers, and other stereoisomers, which are defined as (R)- or (S)- with respect to absolute stereochemistry, or (D)- or (L)- with respect to amino acids. Accordingly, embodiments include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or may be resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). Where a compound described herein contains olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, the compound is intended to include both E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included.

[0121] Embodiments of this disclosure include all forms of rotamers and conformationally restricted states of the compounds of the present invention. Atropisomers are stereoisomers resulting from the inhibition of rotation around a single bond, including cases where steric strain or other contributing factors create a rotational barrier high enough to allow for the isolation of individual conformers. As an example, certain compounds of this disclosure may exist as a mixture of atropisomers or may be purified or concentrated for the presence of a single atropisomer.

[0122] In some embodiments, the compound of formula (I) is a mixture of enantiomers or diastereomers. In other embodiments, the compound of formula (I) is substantially a single enantiomer or diastereomer.

[0123] A "tautomer" refers to a proton shift from one atom in a molecule to another atom in the same molecule. Therefore, embodiments include tautomers of the disclosed compounds.

[0124] The chemical naming protocol and structure diagrams used herein are a modified form of the IUPAC naming system using the ACD / Name Version 9.07 software program and / or the ChemDraw Professional Version 17.0.0.206 software naming program (CambridgeSoft). For complex chemical names used herein, substituents are typically named before the group to which they are bonded. For example, cyclopropylethyl contains an ethyl skeleton with a cyclopropyl substituent. All bonds are identified in the chemical structure diagrams herein, except for all bonds on some carbon atoms that are assumed to be bonded to enough hydrogen atoms to complete valency, unless otherwise stated below.

[0125] "Optional" or "optionally" means that the event or situation described afterward may or may not occur, and that the description includes both cases in which the event or situation occurs and cases in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted, and that the description includes both substituted and unsubstituted aryl radicals.

[0126] The section headings used herein are for organizational purposes only and should not be interpreted as limiting the subjects described.

[0127] Inflammasomes Inflammasomes are multi-protein complexes whose activation plays a central role in innate immunity and inflammation. To date, four inflammasomes have been described: NLRP1, NLRC4, NLRP3, and AIM2. The NLRP3 inflammasome consists of NLRP3, ASC, and caspase-1. Its activation leads to the activation of caspase-1, which promotes the secretion of IL-1β and IL-18, inflammation-mediating cytokines in animal models of several autoimmune diseases, myocardial infarction, metabolic syndromes, inflammatory bowel disease, and macrophage activation syndrome.

[0128] NEK7 is a serine / threonine kinase essential for mitotic entry, cell cycle progression, cell division, and mitotic progression. It is expressed in various tissues, including the brain, heart, lungs, liver, and spleen. Overexpression of NEK7 induces the production of abnormal cells, which are closely associated with tumors such as retinoblastoma, gallbladder cancer, and carcinoma of the head and neck.

[0129] Numerous inhibitors are widely used to disrupt effector signaling pathways involved in IL-1β or IL-18 without eliminating the inflammatory response. Inhibitors of NLRP3 inflammasome activation that block the NLRP3-NEK7 interaction may have therapeutic or prophylactic activity in several human diseases, including type 2 diabetes (T2D), atherosclerosis, gout, and neurodegenerative diseases. However, the precise mechanism of the NLRP3-NEK7 interaction is not well understood.

[0130] Therefore, there is a need to develop inhibitors that directly target NEK7 to influence the inflammatory response regulated by the NLRP3 inflammasome in several pathological diseases, including gout, atherosclerosis, type 2 diabetes, metabolic syndrome, macular degeneration, Alzheimer's disease, multiple sclerosis, and inflammatory bowel disease. Embodiments of this disclosure satisfy this need and provide further relevant advantages.

[0131] Compounds in pharmaceutical compositions This specification describes pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, which can inhibit NEK7 and / or modulate the activity of the NLRP3 inflammasome.

[0132] The embodiments described herein are based on formula (I)

[0133] [ka] We provide compounds having, or pharmaceutically acceptable salts, stereoisomers, or prodrugs thereof, in which, A is C6~C 10 Aryl, C3~C 10 They are cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which has one or more R 6 Then, it is replaced by an optional selection. Y is NH, R 1 is H or C1-C6 alkyl, R 2These are C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. R 3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy. R 4 These are heteroaryls selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, each of which is a halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1 Substitutions are optionally made with one or more substituents selected from C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclylalkyl, and C3-C8 halocycloalkyl, or combinations thereof. R 5 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C10 They are aryl or 5-6 membered heteroaryls, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy. R 6 In each instance, the elements are independently a halo, a C1-C6 alkyl, a cyano, a C1-C6 hydroxylalkyl, a C1-C6 alkoxy, or a C1-C6 haloalkyl.

[0134] In some embodiments of the compound of formula (I), A is C6~C 10 Aryl, C3~C 10 They are cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which has one or more R 6 Then, it is replaced by an optional selection. Y is NH, R 1 is H or C1-C6 alkyl, R 2 These are C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. R 3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy. R 4is heteroaryl selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, each of which is optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and C3-C8 halocycloalkyl, R 5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 member heterocyclyl, C6-C 10 aryl, or 5-6 member heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy, R 6 is, independently at each occurrence, halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0135] In some embodiments of the compound of formula (I), A is C6-C 10 aryl, C3-C 10 cycloalkyl, 3-10 member heterocyclyl, or 5-6 member monocyclic heteroaryl, each of which is optionally substituted with one or more R 6 and is optionally substituted, X is CH or N, Y is NH, R 1 is H or C1-C6 alkyl, R 2is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 member heterocyclyl, or 5-6 member heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 member heterocyclyl, R 3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 member heterocyclyl, or 5-6 member heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy, R 4 is heteroaryl selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, each of which is optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclylalkyl, and C3-C8 halocycloalkyl, R 5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 member heterocyclyl, C6-C 10They are aryl or 5-6 membered heteroaryls, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy. R 6 In each instance, the elements are independently a halo, a C1-C6 alkyl, a C1-C6 alkoxy, a cyano, a C1-C6 hydroxylalkyl, or a C1-C6 haloalkyl.

[0136] In some embodiments, A is any suitable functional group described herein. In some embodiments, A is C6-C 10 Aryl, C3~C 10 They are cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which has one or more R 6 Then, it is optionally replaced. In some embodiments, A is C6~C 10 They are aryl or 5-6 member monocyclic heteroaryls, each of which has one or more R 6 Then, it is optionally replaced. In some embodiments, A is one or more R 6 Then, C6~C will be replaced by any choice. 10 It is an arrow. In some embodiments, A is one or more R 6 The substituted 5-6 member monocyclic heteroaryls are of optional choice. In some embodiments, A is C3-C 10 It is a cycloalkyl group. In some embodiments, A is one or more R 6 These are 3- to 10-member heterocyclines that are optionally substituted.

[0137] In some embodiments, A is a divalent C6 that is optionally substituted. 10It is an aryl ring. In some embodiments, A is a divalent 3- to 8-membered saturated or partially unsaturated carbon ring that is optionally substituted. In some embodiments, A is a divalent 3- to 10-membered heterocycle that is optionally substituted, having 1- to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, A is a divalent 5- to 6-membered monocyclic heteroaryl ring that is optionally substituted, having 1- to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0138] In some embodiments, A is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azosinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolinyl, Nzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, benzimidazolinil, carbazolyl, NH-carbazolyl, carborinil, chromanil, clomenil, cinnolinil, decahydroquinolinil, dithiadinil, tetrahydrofuranil, furanil, flazanil, imidazolidinil, imidazolinil, imidazolyl, 1H-indazolyl, indorenyl, indolinil, indoridinil, indolyl, 3-indolyl, isoindolinil, isoindorenil, isobenzofuranil, isochromanil, isoindazolyl, Isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthilidinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthrolinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, ptery Dinyl, Purinyl, Pyranyl, Pyrazinyl, Pyrazolidinyl, Pyrazolinil, Pyrazolyl, Pyridazinyl, Pyridooxazole, Pyridoimidazole, Pyridothiazol, Pyridinyl, Pyridyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolyl, 2-Pyrrolyl, Pyrrolyl, Quinazolinyl, Quinolinyl, 4H-Quinolidinyl, Quinoxalinyl, Quinuclidinyl, Tetrahydrofuranil, Tetrahydroisoquinolinyl, Tetrahydroquinolinyl, Thiadiandinyl, 1,2,3-Thiadianzolyl, 1,2,4-Thiadianzolyl, 1,2,5-Thiadianzolyl, 1,3,A divalent group selected from 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, and xanthenyl, each of which is optionally substituted.

[0139] In some embodiments, A is a divalent group selected from phenyl, pyridinyl, cyclohexyl, and cyclohexenyl, each of which is optionally substituted. In other embodiments, A is phenyl. In some embodiments, A is saturated or unsaturated cyclohexyl. In further embodiments, A is pyridinyl.

[0140] In some embodiments, A is a pyrimidinyl that is optionally substituted.

[0141] In some embodiments, X is any suitable atom described herein. In some embodiments, X is CH or N. In some embodiments, X is CH. In some embodiments, X is N.

[0142] In some embodiments, Y is any suitable linker described herein. In some embodiments, Y is NH.

[0143] In some embodiments, R 1 R is any suitable functional group as described herein. In some embodiments, R 1 is H. In some embodiments, R 1 is a C1-C6 alkyl group. In some embodiments, R 1 These are methyl, ethyl, n-propyl, or isopropyl.

[0144] In some embodiments, R 2is any suitable functional group described herein. In some embodiments, R 2 R is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. In some embodiments, R 2 R is a C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl, or 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. In some embodiments, R 2 R is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. In some embodiments, R 2 R is cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, or oxetanyl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. In some embodiments, R 2 R is cyclopropyl or oxetanyl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. In some embodiments, R2 is cyclopropyl. In some embodiments, R 2 is oxetanyl. In some embodiments, R 2 R is unsubstituted cyclopropyl or oxetanyl. In some embodiments, R 2 is an N-methyl-substituted pyrrolidinyl. In some embodiments, R 2 It is unsubstituted cyclobutyl.

[0145] In some embodiments, R 2 teeth,

[0146] [ka] That is the case.

[0147] In some embodiments, R 2 teeth,

[0148] [ka] That is the case.

[0149] In some embodiments, R 3 is any suitable functional group described herein. In some embodiments, R 3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy. In some embodiments, R 3 R is H or C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy. In some embodiments, R 3is H. In some embodiments, R 3 is a C1-C6 alkyl group. In some embodiments, R 3 These are methyl, ethyl, n-propyl, or isopropyl.

[0150] In some embodiments, R 4 is any suitable functional group as described herein. In some embodiments, R 4 These are heteroaryl compounds selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, each of which is a halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- Optionally substituted with one or more substituents selected from C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclylalkyl, and C3-C8 halocycloalkyl, or combinations thereof. In some embodiments, R 4These are oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl, or 1,3,4-oxadiazolyl, each of which is a halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxyl Lukyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclylalkyl, and C3-C8 halocycloalkyl, as well as one or more substituents selected from combinations thereof, may be optionally substituted.

[0151] In some embodiments, R 4 is oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, or 1,3,4-oxadiazolyl, each of which is optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclylalkyl, and C3-C8 halocycloalkyl, as well as combinations thereof. In some embodiments, R 4 isoxazolyl is optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and C3-C8 halocycloalkyl.

[0152] In some embodiments, R 4 isoxazolyl is optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclylalkyl, and C3-C8 halocycloalkyl, as well as combinations thereof.

[0153] In some embodiments, R 4 Thiazolyl is optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclylalkyl, and C3-C8 halocycloalkyl, as well as combinations thereof.

[0154] In some embodiments, R 4This refers to isothiazolyls that are optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclylalkyl, and C3-C8 halocycloalkyl, as well as combinations thereof.

[0155] In some embodiments, R 4 1,2,4-thiadiazolyl is optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclylalkyl, and C3-C8 halocycloalkyl, as well as combinations thereof.

[0156] In some embodiments, R 41,3,4-thiadiazolyl is optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclylalkyl, and C3-C8 halocycloalkyl, as well as combinations thereof.

[0157] In some embodiments, R 4 This refers to 1,2,4-triazolyl compounds that are optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclylalkyl, and C3-C8 halocycloalkyl, as well as combinations thereof.

[0158] In some embodiments, R 4 This is 1,3,4-oxadiazolyl, optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, 3-8 membered heterocyclyl, and C3-C8 halocycloalkyl, or combinations thereof.

[0159] In some embodiments, R 4These are substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclylalkyl, and C3-C8 halocycloalkyl, as well as combinations thereof.

[0160] In some embodiments, R 4 teeth,

[0161] [ka] That is the case.

[0162] In some embodiments, R 4 teeth,

[0163] [ka] That is the case.

[0164] In some embodiments, R 4 teeth,

[0165] [ka] That is the case.

[0166] In some embodiments, R 5 is any suitable functional group described herein. In some embodiments, R 5 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 10Aryl, or a 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy. In some embodiments, R 5 is H or C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy. In some embodiments, R 5 is H. In some embodiments, R 5 is C1-C6 alkyl. In some embodiments, R 5 is methyl, ethyl, n-propyl, or isopropyl.

[0167] In some embodiments, each R 6 is any suitable functional group described herein. In some embodiments, each R 6 is independently halo, C1-C6 alkyl, cyano, C1-C6 hydroxylalkyl, C1-C6 alkoxy, or C1-C6 haloalkyl. In some embodiments, each R 6 is chloro or fluoro. In some embodiments, each R 6 is fluoro. In some embodiments, each R 6 is C1-C6 hydroxylalkyl. In some embodiments, each R 6 is C1-C6 hydroxylalkyl. In some embodiments, each R 6 is -CH2CH2OH. In other embodiments, each R 6 is cyano. In some embodiments, each R 6 is C1-C6 alkoxy. In some embodiments, each R 6 is methoxy.

[0168] In some embodiments, A is

[0169] [Chemical formula] is.

[0170] In some embodiments, A is

[0171] [Chemical formula] is.

[0172] In some embodiments, the compound is a compound of formula (Ia)

[0173] [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein R 2a is one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 member heterocyclyl, and is optionally substituted C3-C4 cycloalkyl, R 4a is one or more substituents selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, or C3-C8 haloalkylcycloalkyl, and is optionally substituted isoxazolyl.

[0174] In some embodiments, R 2a is branched C1-C6 alkyl substituted with hydroxyl. In some embodiments, R 2a is C3-C8 cycloalkyl. In some embodiments, R 2a is

[0175] [Chemical formula] is.

[0176] In some embodiments, R 4a is an isoxazolyl substituted with a C3-C8 haloalkylcycloalkyl. In some embodiments, R 4a is a C3-C8 fluoroalkylcycloalkyl. In some embodiments, R 4a is a fluoroalkylcyclopropyl or a fluoroalkylcyclobutyl. In some embodiments, R 4a is

[0177]

Chemical formula

[0178] In some embodiments, the compound is a compound of formula (Ib)

[0179]

Chemical formula

[0180] In some embodiments, the compound of formula (I) is a modulator of the NLRP3 inflammasome.

[0181] In some embodiments, the compound of formula (I) is an inhibitor of NEK7 in a patient or biological sample.

[0182] In various different embodiments, the compound has one of the structures listed in Table 1 below, or a pharmaceutically acceptable salt thereof, stereoisomer, or prodrug.

[0183] In some embodiments, the compound of formula (I) is a compound selected from Table 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments, the compound of formula (I) is selected from the group consisting of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments, the compound of formula (I) is selected from the group consisting of compounds 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments, the compound of formula (I) is selected from compound 10.

[0184] [Table 1-1]

[0185] [Table 1-2]

[0186] [Table 1-3]

[0187] Table 1-4

[0188] Table 1-5

[0189] Table 1-6

[0190] Table 1-7

[0191] Table 1-8

[0192] Table 1-9

[0193] Table 1-10

[0194] Table 1-11

[0195] Table 1-12

[0196] Table 1-13

[0197] [Table 1-14]

[0198] [Table 1-15]

[0199] [Table 1-16]

[0200] [Table 1-17]

[0201] Pharmaceutical composition This specification provides pharmaceutical compositions comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier. A pharmaceutical composition comprises one (or more) of the aforementioned compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. The compounds described herein are formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient.

[0202] In some embodiments, the compounds described herein are formulated into oral dosage forms, including, but not limited to, tablets, powders, pills, sugar-coated tablets, capsules, liquids, gels, syrups, elixirs, slurries, and suspensions. In some embodiments, the compounds described herein are formulated into tablets. In some embodiments, the compounds described herein are formulated into capsules.

[0203] In some embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipients with one or more compounds described herein, and optionally grinding the resulting mixture to process the granular mixture after adding appropriate adjuvants as needed to obtain a tablet or sugar-coated tablet core. Suitable excipients include fillers such as sugars containing lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrants are optionally added. Disintegrants include, but are not limited to, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or sodium alginate, or their salts.

[0204] In one embodiment, dosage forms such as sugar-coated tablet cores and tablets are provided with one or more suitable coatings. In a specific embodiment, concentrated sugar solutions are used to coat the dosage forms. The sugar solutions optionally contain additional components such as gum arabic, talc, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures, just as examples. Dyes and / or pigments are also optionally added to the coating for identification purposes. In addition, dyes and / or pigments are optionally used to characterize different combinations of active compound doses.

[0205] In some embodiments, at least one of the compounds described herein is formulated in therapeutically effective amounts into other oral dosage forms. These oral dosage forms include push-fit capsules made of gelatin, as well as soft-seal capsules made of gelatin and a plasticizer such as glycerol or sorbitol. In specific embodiments, the push-fit capsules contain the active ingredient in a mixture with one or more fillers. Fillers include, but are not limited to, binders such as lactose or starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In other embodiments, the soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, but are not limited to, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. Further stabilizers are optionally added.

[0206] In the treatment methods according to embodiments of the present invention, at least one compound of formula (I) is administered in an effective dose to a subject who is suffering from or has been diagnosed with such a disease, disorder, or medical condition. The effective dose or amount may be determined by methods such as modeling, dose escalation studies, or clinical trials, for example, the mode or route of administration or drug delivery, the pharmacokinetics of the drug, the severity and course of the disease, disorder, or illness, the subject's previous or ongoing treatment, the subject's health status and response to the drug, and the judgment of the treating physician.

[0207] The pharmaceutical compositions described herein can be administered in any appropriate effective dose as described herein. In some embodiments, the pharmaceutical composition contains about 0.1 mg to about 10 mg of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 0.5 mg to about 5 mg of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 5 mg of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 4 mg of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 3 mg of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 2 mg of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 1 mg of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 0.5 mg of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 0.1 mg to about 10 mg of compound 10 as shown in Table 1. In some embodiments, the pharmaceutical composition contains about 0.5 mg to about 5 mg of compound 10. In some embodiments, the pharmaceutical composition contains about 5 mg of compound 10. In some embodiments, the pharmaceutical composition contains about 4 mg of compound 10. In some embodiments, the pharmaceutical composition contains about 3 mg of compound 10. In some embodiments, the pharmaceutical composition contains about 2 mg of compound 10. In some embodiments, the pharmaceutical composition contains about 1 mg of compound 10. In some embodiments, the pharmaceutical composition contains about 0.5 mg of compound 10.

[0208] The pharmaceutical compositions described herein may be administered according to any suitable administration schedule described herein. In some embodiments, the pharmaceutical composition is administered to a subject in a weekly cycle, the weekly cycle consisting of administering the composition for five consecutive days followed by two consecutive days without administering the pharmaceutical composition.

[0209] In some embodiments, the pharmaceutical composition is administered in weekly cycles for at least two weeks. In some embodiments, the pharmaceutical composition is administered in weekly cycles for at least four weeks. In some embodiments, the pharmaceutical composition is administered in weekly cycles for at least eight weeks. In some embodiments, the pharmaceutical composition is administered in weekly cycles for at least twelve weeks. In some embodiments, the pharmaceutical composition is administered in weekly cycles for sixteen weeks. In some embodiments, the pharmaceutical composition is administered in weekly cycles for twenty weeks. In some embodiments, the pharmaceutical composition is administered in weekly cycles for twenty-four weeks. In some embodiments, the pharmaceutical composition is administered in weekly cycles for twenty-eight weeks. In some embodiments, the pharmaceutical composition is administered in weekly cycles for thirty-two weeks.

[0210] In some embodiments, the pharmaceutical composition is administered to the subject daily. In some embodiments, the pharmaceutical composition is administered to the subject once daily.

[0211] In some embodiments, the pharmaceutical composition is administered to the subject once daily for at least two weeks. In some embodiments, the pharmaceutical composition is administered once daily for at least four weeks. In some embodiments, the pharmaceutical composition is administered once daily for at least eight weeks. In some embodiments, the pharmaceutical composition is administered once daily for at least twelve weeks. In some embodiments, the pharmaceutical composition is administered once daily for sixteen weeks. In some embodiments, the pharmaceutical composition is administered once daily for twenty weeks. In some embodiments, the pharmaceutical composition is administered once daily for twenty-four weeks. In some embodiments, the pharmaceutical composition is administered once daily for twenty-eight weeks. In some embodiments, the pharmaceutical composition is administered once daily for thirty-two weeks. In some embodiments, the compound of formula (I) is administered to the subject daily. In some embodiments, the compound of formula (I) is administered to the subject once daily.

[0212] In some embodiments, the compound of formula (I) is administered to the subject once daily for at least two weeks. In some embodiments, the compound of formula (I) is administered once daily for at least four weeks. In some embodiments, the compound of formula (I) is administered once daily for at least eight weeks. In some embodiments, the compound of formula (I) is administered once daily for at least twelve weeks. In some embodiments, the compound of formula (I) is administered once daily for sixteen weeks. In some embodiments, the compound of formula (I) is administered once daily for twenty weeks. In some embodiments, the compound of formula (I) is administered once daily for twenty-four weeks. In some embodiments, the compound of formula (I) is administered once daily for twenty-eight weeks. In some embodiments, the compound of formula (I) is administered once daily for thirty-two weeks. In some embodiments, the compound of formula (I) is administered once daily for one to twelve weeks. In some embodiments, the compound of formula (I) is administered for twelve weeks.

[0213] In some embodiments, the compound of formula (I) is administered once daily at a dose of approximately 2 mg for 1 to 12 weeks. In some embodiments, the compound of formula (I) is administered once daily at a dose of approximately 3 mg for 1 to 12 weeks. In some embodiments, the compound of formula (I) is administered once daily at a dose of approximately 4 mg for 1 to 12 weeks. In some embodiments, the compound of formula (I) is administered once daily at a dose of approximately 5 mg for 1 to 12 weeks.

[0214] In some embodiments, compound 10 is administered to the subject daily. In some embodiments, compound 10 is administered to the subject once daily.

[0215] In some embodiments, compound 10 is administered to the subject once daily for at least two weeks. In some embodiments, compound 10 is administered once daily for at least four weeks. In some embodiments, compound 10 is administered once daily for at least eight weeks. In some embodiments, compound 10 is administered once daily for at least twelve weeks. In some embodiments, compound 10 is administered once daily for sixteen weeks. In some embodiments, compound 10 is administered once daily for twenty weeks. In some embodiments, compound 10 is administered once daily for twenty-four weeks. In some embodiments, compound 10 is administered once daily for twenty-eight weeks. In some embodiments, compound 10 is administered once daily for thirty-two weeks. In some embodiments, compound 10 is administered once daily for one to twelve weeks. In some embodiments, compound 10 is administered for twelve weeks.

[0216] In some embodiments, compound 10 is administered once daily at a dose of approximately 2 mg for 1 to 12 weeks. In some embodiments, compound 10 is administered once daily at a dose of approximately 3 mg for 1 to 12 weeks. In some embodiments, compound 10 is administered once daily at a dose of approximately 4 mg for 1 to 12 weeks. In some embodiments, compound 10 is administered once daily at a dose of approximately 5 mg for 1 to 12 weeks.

[0217] The pharmaceutical composition may be in any suitable carrier for oral administration as described herein. In some embodiments, the pharmaceutical composition is in a capsule. In some embodiments, the capsule is a hard gelatin capsule. In some embodiments, the capsule is a size 1, 2, or 3 capsule. In some embodiments, the capsule is a size 1 capsule. In some embodiments, the capsule is a size 2 capsule. In some embodiments, the capsule is a size 3 capsule.

[0218] The capsules may have any suitable color as described herein. In some embodiments, the capsules are opaque white, Swedish orange, or dark green. In some embodiments, the capsules are opaque white. In some embodiments, the capsules are Swedish orange. In some embodiments, the capsules are dark green.

[0219] In some embodiments, the pharmaceutical composition is a tablet. In some embodiments, the tablet is a film-coated tablet. In some embodiments, the tablet is an immediate-release tablet. In some embodiments, the tablet is a film-coated immediate-release tablet. In some embodiments, the tablet is coated with Opadry II. In some embodiments, the tablet is coated with Opadry II Yellow. In some embodiments, the tablet is coated with Opadry II Red. In some embodiments, the tablet has a diameter of about 7 mm.

[0220] The pharmaceutically acceptable excipients in the pharmaceutical compositions described herein may be any suitable pharmaceutically acceptable excipients. In some embodiments, the pharmaceutically acceptable excipients are sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, magnesium stearate, or a combination of two or more thereof. In some embodiments, the pharmaceutically acceptable excipients include at least two components selected from the group consisting of sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, and magnesium stearate. In some embodiments, the pharmaceutically acceptable excipients include at least three components selected from the group consisting of sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, and magnesium stearate. In some embodiments, pharmaceutically acceptable excipients include at least four components selected from the group consisting of sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, and magnesium stearate. In some embodiments, a pharmaceutically acceptable excipient comprises at least five components selected from the group consisting of sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, and magnesium stearate. In some embodiments, a pharmaceutically acceptable excipient comprises at least six components selected from the group consisting of sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, and magnesium stearate. In some embodiments, a pharmaceutically acceptable excipient comprises sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, and magnesium stearate.

[0221] In some embodiments, sodium lauryl sulfate is Kolliphore SLS fine. In some embodiments, partially gelatinized corn starch is Starch 1500. In some embodiments, microcrystalline cellulose is Avicel PH101. In some embodiments, sodium starch glycolate is Type A. In some embodiments, hydroxypropyl cellulose LF is Klucel HPC LF. In some embodiments, colloidal silicon dioxide is Aerosil Pharma 200. In some embodiments, pharmaceutically acceptable excipients are sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, and magnesium stearate. In some embodiments, sodium lauryl sulfate is Kolliphore SLS fine, partially gelatinized corn starch is Starch 1500, microcrystalline cellulose is Avicel PH 101, sodium starch glycolate is Type A, hydroxypropyl cellulose LF is Klucel HPC LF, and colloidal silicon dioxide is Aerosil Pharma 200.

[0222] pharmaceutically acceptable excipients may have any appropriate amounts as specified herein. The wt% measurement of excipients in tablets (%w / w) refers to the weight percentage of each excipient relative to the total weight of the core tablet before coating. The wt% measurement of excipients in capsules (%w / w) refers to the weight percentage of each excipient relative to the total weight of all components excluding the outer capsule itself.

[0223] In some embodiments, the amount of sodium lauryl sulfate is about 0.01% w / w to about 0.1% w / w. In some embodiments, the amount of sodium lauryl sulfate is about 0.01% w / w to about 0.8% w / w. In some embodiments, the amount of sodium lauryl sulfate is about 0.02% w / w to about 0.6% w / w. In some embodiments, the amount of sodium lauryl sulfate is about 0.04% w / w.

[0224] In some embodiments, the amount of partially gelatinized corn starch is about 30% w / w to about 50% w / w. In some embodiments, the amount of partially gelatinized corn starch is about 40% w / w to about 50% w / w. In some embodiments, the amount of partially gelatinized corn starch is about 40% w / w to about 45% w / w. In some embodiments, the amount of partially gelatinized corn starch is about 43% w / w to about 44% w / w.

[0225] In some embodiments, the amount of microcrystalline cellulose is about 30% w / w to about 50% w / w. In some embodiments, the amount of microcrystalline cellulose is about 40% w / w to about 50% w / w. In some embodiments, the amount of microcrystalline cellulose is about 42% w / w to about 50% w / w. In some embodiments, the amount of microcrystalline cellulose is about 44% w / w to about 48% w / w.

[0226] In some embodiments, the amount of sodium starch glycolate is about 1% w / w to about 5% w / w. In some embodiments, the amount of sodium starch glycolate is about 2% w / w to about 4% w / w. In some embodiments, the amount of sodium starch glycolate is about 3% w / w to about 4% w / w.

[0227] In some embodiments, the amount of hydroxypropylcellulose LF is about 1% w / w to about 5% w / w. In some embodiments, the amount of hydroxypropylcellulose LF is about 1% w / w to about 4% w / w. In some embodiments, the amount of hydroxypropylcellulose LF is about 2% w / w to about 3% w / w.

[0228] In some embodiments, the amount of colloidal silicon dioxide is about 0.5% w / w to about 5% w / w. In some embodiments, the amount of colloidal silicon dioxide is about 0.5% w / w to about 3% w / w. In some embodiments, the amount of colloidal silicon dioxide is about 0.5% w / w to about 1.5% w / w. In some embodiments, the amount of colloidal silicon dioxide is about 1% w / w to about 1.5% w / w. In some embodiments, the amount of colloidal silicon dioxide is about 1% w / w to about 1.2% w / w.

[0229] In some embodiments, the amount of sodium lauryl sulfate is about 0.04% w / w, the amount of partially gelatinized corn starch is about 43% w / w to about 44% w / w, the amount of microcrystalline cellulose is about 44% w / w to about 48% w / w, the amount of sodium starch glycolate is about 3% w / w to about 4% w / w, the amount of hydroxypropyl cellulose LF is about 2% w / w to about 3% w / w, the amount of colloidal silicon dioxide is about 1% w / w to about 1.5% w / w, and the amount of magnesium stearate is about 1% w / w to about 1.5% w / w.

[0230] In some embodiments, the pharmaceutical composition of the compound of formula (I) is a modulator of the NLRP3 inflammasome. In some embodiments, the pharmaceutical composition of the compound of formula (I) inhibits NEK7 when administered to a patient or biological sample.

[0231] Treatment method The embodiments of the pharmaceutical compositions described herein are useful as NEK7 inhibitors in host species. Pharmaceutical compositions comprising the compound of formula (I) may be allosteric inhibitors of NEK7. Compounds of formula (I) can also inhibit other receptors such as Toll-like receptors (TLRs) and the interleukin family. Pharmaceutical compositions comprising the compound of formula (I) are also useful for treating conditions mediated by effector signaling molecules such as Il-β and IL-18. The host or patient may belong to any mammalian species, such as primates, particularly humans, mice, rats, and rodents including hamsters, rabbits, horses, cattle, dogs, cats, etc. Animal models are of interest for experimental investigations that provide models for the treatment of human diseases.

[0232] This specification describes pharmaceutical compositions useful as inhibitors of the NLRP3 inflammasome activation mechanism. Therefore, compounds of formula (I) are also useful in treating conditions resulting from its activation in host species.

[0233] The embodiments of the pharmaceutical compositions described herein are useful as inhibitors of NLRP3 (protein)-NEK7 (protein) interactions. Therefore, in some embodiments, the compounds are also useful in treating conditions resulting from NLRP3-NEK7 association in host species.

[0234] Embodiments of the pharmaceutical composition are useful for treating human conditions mediated by effectors selected from the group consisting of IL-β, IL-18, and caspase-1. The pharmaceutical composition may be useful as a potent inhibitor of the interleukin family, for example, in a non-limiting example, as a potent inhibitor of IL-1 family cytokine production. The common interleukin family includes, but is not limited to, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, and IL-17.

[0235] Embodiments herein also relate to the use of pharmaceutical compositions, and / or physiologically acceptable salts thereof, for the prophylactic or therapeutic treatment and / or monitoring of diseases caused, mediated, and / or regulated by NLRP3 inflammasome activity. Furthermore, embodiments herein relate to the use of pharmaceutical compositions, and / or physiologically acceptable salts thereof, for the manufacture of pharmaceuticals for the prophylactic or therapeutic treatment and / or monitoring of diseases caused, mediated, and / or regulated by NLRP3 inflammasome activity. In certain embodiments, the disclosure provides the use of pharmaceutical compositions for the manufacture of pharmaceuticals for the prophylactic or therapeutic treatment of NLRP3-mediated disorders.

[0236] This specification describes a method for treating an inflammatory disease or illness mediated by the NLRP3 inflammasome, which involves administering a therapeutically effective dose of one of the pharmaceutical compositions described herein to a patient in need of treatment.

[0237] In some embodiments, diseases that can be treated with the pharmaceutical compositions described herein include type II diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue injury caused by infection, gout, arthritis, enteritis, hepatitis, peritonitis, silicosis, UV-induced sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative diseases, multiple sclerosis, and Mackle-Wells syndrome.

[0238] In some embodiments, the pharmaceutical composition is used in methods for treating disorders or diseases selected from autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial and viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, transplantation, sperm motility, anemia, graft rejection, lung injury, respiratory diseases, ischemic conditions, and cancer. In some more specific embodiments, the compound of formula (I) is used in methods for treating myelodysplastic syndrome (MDS).

[0239] In some embodiments, pharmaceutical compositions comprising the compound of formula (I) are useful for treating subjects having MDS. Subjects may have various types of MDS. In non-limiting examples, subjects may have a documented diagnosis of MDS, non-proliferative myelodysplastic / myeloproliferative neoplasm (MDS / MPN), MDS with hypoblasts, MDS with blast cell proliferation, hypoplastic MDS, mutations in MDS with hypoblasts such as isolated deletion or mutation, and leukemia such as chronic myelomonocytic leukemia. In some embodiments, pharmaceutical compositions comprising the compound of formula (I) are useful for treating subjects having very low-risk to medium-risk MDS, subjects may also have symptomatic anemia. In some embodiments, the compound of formula (I) is compound 10, and the subject is treated with 0.5 mg to 5 mg of compound 10 (e.g., 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg). The subject may be administered compound 10 daily for, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks, or longer.

[0240] In some embodiments, subjects with MDS or at risk of MDS are refractory, intolerant, or unsuitable for treatment with erythrocyte stimulants (ESAs). In some embodiments, the subjects are refractory to ESA treatment. In some embodiments, the subjects are intolerant to ESA treatment. In some embodiments, the subjects are unsuitable for ESA treatment. In some embodiments, the subjects are non-responsive to ESA treatment. In some embodiments, the subjects have discontinued ESA treatment for at least two weeks prior to administration of a pharmaceutical composition containing a compound of formula (I) (e.g., compound 10).

[0241] In some embodiments, NEK7-related disorders treatable with the pharmaceutical compositions described herein are selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmuneglobulinemia D and periodic fever syndromes, cryopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (Deficiency of IL-1 Receptor Antagonist), Alzheimer's disease, Parkinson's disease, and cancer.

[0242] This specification provides a method for treating a disease or disorder in a subject requiring treatment of such disease or disorder, the method comprising administering to the subject a therapeutically effective dose of a pharmaceutical composition described herein.

[0243] In some embodiments, the disease or disorder is an NLRP3-mediated disease or disorder. In some embodiments, NLRP3-mediated diseases or disorders are myelodysplastic syndromes, inflammatory diseases or disorders, autoimmune diseases or disorders, cardiovascular diseases, neurodegenerative diseases or disorders, bacterial and / or viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, anemia, graft rejection, lung injury, respiratory diseases, ischemic conditions, or a combination thereof.

[0244] In some embodiments, the NLRP3-mediated disease or disorder is a myelodysplastic syndrome or an inflammatory disease or disorder. In some embodiments, the NLRP3-mediated disease or disorder is a myelodysplastic syndrome. In some embodiments, the myelodysplastic syndrome is a myelodysplastic syndrome with multiple systemic dysplasia, a myelodysplastic syndrome with monosystemic dysplasia, a myelodysplastic syndrome with ring sideroblasts, a myelodysplastic syndrome with blast plasia, a myelodysplastic syndrome with a single deletion, or an unclassifiable myelodysplastic syndrome.

[0245] In some embodiments, the NLRP3-mediated disease or disorder is an inflammatory disease or disorder. In some embodiments, the inflammatory disease or disorder is acute inflammatory pain.

[0246] In some embodiments, methods for treating myelodysplastic syndrome (MDS) in subjects requiring treatment for myelodysplastic syndrome (MDS) are described herein, the methods comprising:

[0247] [ka] The process includes administering the compound, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. During the ceremony, A is C6~C 10 Aryl, C3~C 10 They are cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which has one or more R 6 Then, it is replaced by an optional selection. X is either CH or N. Y is NH, R 1 H is H, R 2These are C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl, or 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. R 3 H is H, R 4 These are heteroaryls selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, each of which is a halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkyl Optionally substituted with one or more substituents selected from nyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclyl, and C3-C8 halocycloalkyl. R 5 H is H, Each R 6 These are independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl, or C1-C6 haloalkyl. Here, (i) The subjects are those who have symptomatic anemia, (ii) The subjects are refractory, intolerant, or ineligible for treatment with erythropoiesis-stimulating agents (ESAs), and are selected on an optional basis to have discontinued previous ESA treatment at least two weeks prior to the administration step. (iii) The subjects have very low-risk MDS, low-risk MDS, or medium-risk MDS, (iv) The administration step involves orally administering the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to the subject. (v) The administration step involves administering the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to the subject on a daily basis, or (vi) A combination of two or more of (i) to (v). In some embodiments, the compound of formula (I) is compound 10, and the subject is treated with 0.5 mg to 5 mg of compound 10 (e.g., 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg). The subject may be administered compound 10 daily for, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks, or longer.

[0248] Examples The following exemplary embodiments are representative of, and not intended to limit, embodiments of the stimuli, systems, and methods described herein.

[0249] Example 1. Composition of capsule The following table provides compositions of compound 10, which is an active ingredient, in various amounts for treating patients by modulating the NLRP3 inflammasome to treat the disease.

[0250] [Table 2]

[0251] [Table 3]

[0252] [Table 4]

[0253] [Table 5]

[0254] Example 2. Tablet composition The following table provides compositions of compound 10, which is an active ingredient, in various amounts for treating patients by modulating the NLRP3 inflammasome to treat the disease.

[0255] [Table 6]

[0256] The compound 10 formulation is supplied as immediate-release film-coated tablets containing 0.5 or 2 mg of the active ingredient, compound 10. Both strength tablets are supplied as round-shaped tablets with a flat-faced diameter of 7 mm, with a core tablet weight of 140 mg. They are distinguished by their film coating color—0.5 mg tablets are film-coated in yellow, and 2 mg tablets are film-coated in red. Similarly, to support clinical trials, film-coated placebo tablets of a size, shape, and color suitable for the 0.5 mg and 2 mg active tablets are manufactured.

[0257] [Table 7]

[0258] [Table 8]

[0259] [Table 9]

[0260] [Table 10]

[0261] [Table 11]

[0262] [Table 12]

[0263] Overall stability of active tablets of compound 10 (0.5 mg and 2.0 mg) The clinical formulations of compound 10 as tablets of either 0.5 mg or 2 mg strength are stable, and no degradation trends were observed during formulation development, as shown in Tables 11 and 12 from the prototype / development batch. This study was conducted for 3 months under both long-term conditions of 25°C / 60%RH and accelerated conditions of 40°C / 75%RH after packaging the tablets in HDPE bottles.

[0264] Data from the technical batches indicate that both 0.5 mg and 2 mg strengths of the active drug product were stable throughout a 3-month test under all storage conditions. No new impurities were detected, and some individual impurities, as well as some total impurities, increased slightly, particularly under accelerated storage conditions. However, all values ​​for impurities and other test parameters were good within the specification. This data supports the proposed long-term storage of compound 10 in HDPE bottles at controlled room temperature (20-25°C).

[0265] Example 3. Pharmacokinetics of Compound 10 The subjects were treated with compound 10 at doses of 1 mg to 4 mg for two weeks, in a 5-day on-cycle and 2-day off-cycle. The following table shows the obtained PK parameters.

[0266] [Table 13]

[0267] The plasma concentration-time profile is shown in Figure 1.

[0268] Example 4. Clinical trial of a pharmaceutical formulation of compound 10. The subjects were treated with a pharmaceutical composition containing one of the compounds listed in Tables 2-4. The subjects were treated with the pharmaceutical composition once daily for 5 days, followed by a 2-day break for a 1-week treatment cycle. This treatment cycle was repeated for up to 16 weeks, and could be extended for another 16 weeks in the event of a positive response. For some subjects, blood (plasma) could be collected before the start of each cycle to determine the trough concentration of compound 10.

[0269] The subjects are selected according to the following criteria: 1. Documented diagnosis of MDS or non-proliferative (WBC < 13,000 / μL) myelodysplastic / myeloproliferative neoplasms (MDS / MPN) according to the World Health Organization (WHO) 2022 classification and the Revised International Prognostic Scoring System (IPSS-R) classification for very low-risk, low-risk, or intermediate-risk diseases. According to the WHO 2022 criteria, the following MDS subjects are eligible. MDS with hypoblasts and isolated 5q deletion (MDS-5q) MDS with hypoblasts and SF3B1 mutation (MDS-SF3B1) MDS with hypoblasts (MDS-LB) MDS, hypoplastic (MDS-h) MDS with increased blast cells (MDS-IB): MDS-IB1 In accordance with the WHO 2022 criteria, the following non-proliferative MDS / MPN patients are eligible. Chronic myelomonocytic leukemia Myelodysplasia / Myeloproliferative Neoplasm with Neutrophilia Myelodysplastic / myeloproliferative neoplasms with SF3B1 mutations and thrombocytosis Unless otherwise specified, myelodysplastic / myeloproliferative neoplasms Less than 2.10% of bone marrow osteoblasts 3. Unresponsive to, intolerant to, or unsuitable for treatment with erythrocyte stimulants (ESAs) as defined by any of the following: a) Unresponsive to prior ESA treatment: Pre-treatment with ESA that does not respond to ESA alone or in combination with myeloproliferative factors (must have received recombinant erythropoietin (rHu EPO) at epoetin alfa ≥ 40,000 IU / week for > 8 weeks, or darbepoetin alfa 300-500 μg Q2-3W for > 8 weeks) or ESA that no longer responds to prior treatment with ESA. b) Intolerance to prior ESA treatment: Intolerance to prior ESA treatment, with documentation of discontinuation due to intolerance or adverse events. c) ESA ineligibility: Subjects who have not been previously treated with ESA may be ineligible for ESA due to a low probability of response to ESA based on endogenous serum erythropoietin levels >200 U / L.

[0270] Example 5. Phase II Study of Compound 10, an NLRP3 inflammasome and midosome inhibitor, in patients with low-risk or intermediate-risk myelodysplastic syndrome (MDS) The compounds described herein include first-in-class allosteric inhibitors of the inflammasome scaffold protein NEK7. Compound 10 is used in clinical trials as a representative of the class. By inducing conformational changes that interfere with the NEK7-NLRP3 interaction required for NLRP3 inflammasome assembly and IRAK1 / 4 activation, compound 10 inhibits both Toll-like receptor (TLR) priming and NLRP3 inflammasome complex assembly. Unlike NLRP3, compound 10, being an ATPase-targeted inhibitor, effectively eliminates NLRP3 activation and induces degradation of the activated inflammasome complex and circulating ASC speckles. This results in potent inhibition of IL-1 family cytokine production (IC50 value of IL-1β release = 22 nM in THP-1 differentiated macrophages) and suppression of pyroptosis. The NLRP3 inflammasome is a key biological driver of ineffective hematopoiesis in MDS and is enhanced by non-standard IRAK1 / 4 signaling, which propagates leukemia stem cell regeneration.

[0271] The first human Phase I trial conducted in normal volunteers showed that compound 10 was readily absorbed orally, had a long elimination half-life, and effectively blocked NLRP3 inflammasome activation at low doses.

[0272] The Phase IIa trial will evaluate the efficacy, safety, and pharmacodynamics of compound 10 administered to up to 40 adult patients with a diagnosis of very low-risk, low-risk, or intermediate-risk myelodysplastic syndrome (MDS) and symptomatic anemia, as defined by the Revised International Prognostic Scoring System (IPSS-R).

[0273] All subjects must sign informed consent, have symptomatic anemia, be refractory, intolerant, or ineligible for treatment with erythrocyte stimulants (ESAs), and discontinue any prior ESA treatment at least two weeks prior to the study treatment. The study will measure the rate of hematological improvement (according to IWG 2018 criteria), including transfusion dependence and changes in hemoglobin levels, as the primary study endpoints. Secondary endpoints will further evaluate safety and tolerance, the effect of compound 10 on biomarkers of inflammasome activation, and changes in clonal size as measured by mutation variant allele frequency of somatic genes. Compound 10 will be administered orally in a 28-day cycle, with a schedule of 5 days on and 2 days off per week. From cycle 5 to cycle 8, weekly subcutaneous (SC) administration of epoetin alfa, or every two weeks via SC, is acceptable in subjects who do not respond to compound 10 monotherapy at week 16.

[0274] Example 6. Phase II trial of compound 10, an NLRP3 inflammasome and midosome inhibitor, in patients with low-risk or intermediate-risk myelodysplastic syndrome (MDS). The compounds described herein include first-in-class allosteric inhibitors of the inflammasome scaffold protein NEK7. Compound 10 is used clinically as a representative of this class. By inducing conformational changes that disrupt the NEK7-NLRP3 interaction required for NLRP3 inflammasome assembly and IRAK1 / 4 activation, compound 10 inhibits both Toll-like receptor (TLR) priming and NLRP3 inflammasome complex assembly. Unlike NLRP3, compound 10, being an ATPase-targeted inhibitor, effectively eliminates NLRP3 activation and induces disassembly of the activated inflammasome complex and circulating ASC speckles. This results in potent inhibition of IL-1 family cytokine production (IC50 value = 22 nM for IL-1β release in THP-1 differentiated macrophages) and suppression of pyroptosis. The NLRP3 inflammasome is a key biological driver of ineffective hematopoiesis in MDS, which is enhanced by non-standard IRAK1 / 4 signaling that propagates leukemia stem cell autoregeneration.

[0275] A first-in-human phase I study conducted in normal volunteers showed that compound 10 was readily absorbed orally, had a long elimination half-life, and effectively blocked NLRP3 inflammasome activation at low doses.

[0276] The Phase IIa trial will evaluate the efficacy, safety, and pharmacodynamics of compound 10 administered to up to 40 adult patients with a diagnosis of very low-risk, low-risk, or intermediate-risk myelodysplastic syndrome (MDS) and symptomatic anemia, as defined by the Revised International Prognostic Scoring System (IPSS-R).

[0277] All subjects have signed informed consent, have symptomatic anemia, are refractory, intolerant, or ineligible for treatment with erythrocyte stimulants (ESAs), and have discontinued prior ESAs at least two weeks prior to the study treatment. The study will measure the rate of hematological improvement (according to IWG 2018 criteria), including transfusion dependence and changes in hemoglobin levels, as the primary endpoint. Secondary endpoints will further evaluate safety and tolerance, the effect of compound 10 on biomarkers of inflammasome activation, and changes in clonal size as measured by the frequency of mutant variant alleles in somatic genes. Compound 10 will be administered daily at an oral dose of 4 mg for up to 12 weeks.

[0278] Example 7. Phase II trial of compound 10, an NLRP3 inflammasome and midosome inhibitor, in patients with low-risk or intermediate-risk myelodysplastic syndrome (MDS). The compounds described herein include first-in-class allosteric inhibitors of the inflammasome scaffold protein NEK7. Compound 10 is used clinically as a representative of this class. By inducing conformational changes that interfere with the NEK7-NLRP3 interaction required for NLRP3 inflammasome assembly and IRAK1 / 4 activation, compound 10 inhibits both Toll-like receptor (TLR) priming and NLRP3 inflammasome complex assembly. Unlike NLRP3, compound 10, being an ATPase-targeted inhibitor, effectively eliminates NLRP3 activation and induces degradation of the activated inflammasome complex and circulating ASC speckles. This results in potent inhibition of IL-1 family cytokine production (IC50 value = 22 nM for IL-1β release in THP-1 differentiated macrophages) and suppression of pyroptosis. The NLRP3 inflammasome is a key biological driver of ineffective hematopoiesis in MDS and is enhanced by non-standard IRAK1 / 4 signaling that propagates leukemia stem cell autoregeneration.

[0279] A first-in-human Phase I trial conducted in normal volunteers showed that compound 10 was readily absorbed orally, had a long elimination half-life, and effectively blocked NLRP3 inflammasome activation at low doses.

[0280] The Phase IIa trial will evaluate the efficacy, safety, and pharmacodynamics of compound 10 administered to up to 40 adult patients with a diagnosis of very low-risk, low-risk, or intermediate-risk myelodysplastic syndrome (MDS) and symptomatic anemia, as defined by the Revised International Prognostic Scoring System (IPSS-R).

[0281] All subjects have signed informed consent, have symptomatic anemia, are refractory, intolerant, or ineligible for treatment with erythrocyte stimulants (ESAs), and have discontinued prior ESA treatment at least two weeks prior to the study treatment. The study will measure the rate of hematological improvement (according to IWG 2018 criteria), including transfusion dependence and changes in hemoglobin levels, as the primary endpoint. Secondary endpoints will further evaluate safety and tolerance, the effect of compound 10 on biomarkers of inflammasome activation, and changes in clonal size as measured by the frequency of mutant variant alleles in somatic genes. Compound 10 will be administered daily at an oral dose of 5 mg for up to 12 weeks.

[0282] Numbered embodiments Some numbered examples of embodiments are shown below.

[0283] (1) Equation (I)

[0284] [ka] A pharmaceutical composition comprising a compound thereof, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and at least one pharmaceutically acceptable excipient, During the ceremony, A is C6~C 10 Aryl, C3~C 10They are cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which has one or more R 6 Then, it is replaced by an optional selection. X is either CH or N. Y is NH, R 1 H is H, R 2 These are C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl, or 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. R 3 H is H, R 4 These are heteroaryls selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, each of which is a halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkyl Optionally substituted with one or more substituents selected from nyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclyl, and C3-C8 halocycloalkyl. R 5 H is H, Each R 6These are independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl, or C1-C6 haloalkyl. Here, the pharmaceutical composition is a pharmaceutical composition containing formula (I) in an amount of 10 mg or less.

[0285] (2)R 2 The pharmaceutical composition according to Embodiment 1, wherein is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl.

[0286] (3)R 2 teeth,

[0287] [ka] The pharmaceutical composition according to Embodiment 1 or 2.

[0288] (4)R 4These are oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl, or 1,3,4-oxadiazolyl, each of which is a halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyano A pharmaceutical composition according to any one of Embodiments 1 to 3, wherein the substituents are optionally substituted with alkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclyl, and C3-C8 halocycloalkyl, and one or more substituents selected from combinations thereof.

[0289] (5)R 4 The pharmaceutical composition according to Embodiment 4, wherein is substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclyl, or C3-C8 halocycloalkyl, or a combination thereof.

[0290] (6)R 4 The structure is as follows:

[0291] [ka] A pharmaceutical composition according to any one of embodiments 1 to 5, having one of the following:

[0292] (7) A is C6~C 10 Aryl, C3~C10 Cycloalkyl or 5-6 membered monocyclic heteroaryl, each of which contains one or more R 6 The pharmaceutical composition according to any one of Embodiments 1 to 6, which is optionally substituted.

[0293] (8) The pharmaceutical composition according to Embodiment 1, wherein A is cyclohexyl, cyclohexenyl, phenyl, pyridinyl, or pyrimidinyl.

[0294] (9) The pharmaceutical composition according to Embodiment 8, wherein A is phenyl.

[0295] (10) The pharmaceutical composition according to any one of Embodiments 1 to 9, wherein A is unsubstituted.

[0296] (11) A is one or more R 6 A pharmaceutical composition according to any one of Embodiments 1 to 9, which is replaced by [the specified substance].

[0297] (12)R 6 The pharmaceutical composition of Embodiment 11, wherein is chloro, fluoro, -CHF2, -CH2CH2OH, cyano, or methoxy.

[0298] (13) A is,

[0299] [ka] A pharmaceutical composition according to any one of Embodiments 1 to 12.

[0300] (14) The compound is of formula (Ia)

[0301] [ka] A compound of, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, During the ceremony, R 2aThis is a C3-C4 cycloalkyl that is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. R 4a The pharmaceutical composition according to Embodiment 1, wherein is an isoxazolyl optionally substituted with one or more substituents selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, or C3-C8 haloalkylcycloalkyl.

[0302] (15)R 2a The pharmaceutical composition according to Embodiment 1, wherein is cyclopropyl.

[0303] (16)R 4a teeth,

[0304] [ka] The pharmaceutical composition according to Embodiment 1 or 15.

[0305] (17) A pharmaceutical composition according to any one of Embodiments 1 to 16, wherein the compound of formula (I) is listed in Table 1 or a pharmaceutically acceptable salt or solvate thereof.

[0306] (18) The pharmaceutical composition according to any one of Embodiments 1 to 17, comprising about 0.5 mg to about 5 mg of the compound of formula (I).

[0307] (19) The pharmaceutical composition according to Embodiment 18, comprising about 5 mg of the compound of formula (I).

[0308] (20) The pharmaceutical composition according to Embodiment 18, comprising about 4 mg of the compound of formula (I).

[0309] (21) The pharmaceutical composition according to Embodiment 18, comprising about 3 mg of the compound of formula (I).

[0310] (22) The pharmaceutical composition according to Embodiment 18, comprising about 2 mg of the compound of formula (I).

[0311] (23) The pharmaceutical composition according to Embodiment 18, comprising about 1 mg of the compound of formula (I).

[0312] (24) The pharmaceutical composition according to Embodiment 18, comprising about 0.5 mg of the compound of formula (I).

[0313] (25) The pharmaceutical composition according to any one of Embodiments 1 to 24, wherein the pharmaceutical composition is administered to a subject in a weekly cycle, and the weekly cycle consists of administering the composition for five consecutive days, followed by not administering the pharmaceutical composition for two consecutive days.

[0314] (26) The pharmaceutical composition according to Embodiment 25, which is administered in a 1-week cycle for at least 2 weeks.

[0315] (27) The pharmaceutical composition according to Embodiment 26, which is administered in a 4-week, 1-week cycle.

[0316] (28) The pharmaceutical composition according to Embodiment 26, which is administered in a 1-week cycle for 16 weeks.

[0317] (29) The pharmaceutical composition according to Embodiment 26, which is administered in a 32-week, 1-week cycle.

[0318] (30) The pharmaceutical composition according to any one of Embodiments 1 to 29, wherein the pharmaceutical composition is contained in a capsule.

[0319] (31) The pharmaceutical composition according to Embodiment 30, wherein the capsule is a hard gelatin capsule.

[0320] (32) The pharmaceutical composition according to Embodiment 31, wherein the capsule is a size 3 capsule.

[0321] (33) The pharmaceutical composition according to Embodiment 32, wherein the capsule is opaque white, Swedish orange, or dark green.

[0322] (34) The pharmaceutical composition according to any one of Embodiments 1 to 33, wherein pharmaceutically acceptable excipients are sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, and magnesium stearate.

[0323] (35) The pharmaceutical composition according to Embodiment 34, wherein the sodium lauryl sulfate is Kolliphore SLS fine, the partially gelatinized corn starch is Starch 1500, the microcrystalline cellulose is Avicel PH 101, the sodium starch glycolate is Type A, the hydroxypropyl cellulose LF is Klucel HPC LF, and the colloidal silicon dioxide is Aerosil Pharma 200.

[0324] (36) The pharmaceutical composition according to Embodiment 34 or 35, wherein sodium lauryl sulfate is present in an amount of about 0.01% w / w to about 0.1% w / w.

[0325] (37) The pharmaceutical composition according to Embodiment 36, wherein sodium lauryl sulfate is present in an amount of approximately 0.04% w / w.

[0326] (38) The pharmaceutical composition according to any one of embodiments 34 to 37, wherein the amount of partially gelatinized corn starch is about 30% w / w to about 50% w / w.

[0327] (39) The pharmaceutical composition of Embodiment 38, wherein the amount of partially gelatinized corn starch is approximately 43% w / w to approximately 44% w / w.

[0328] (40) The pharmaceutical composition according to any one of Embodiments 34 to 39, wherein the amount of microcrystalline cellulose is approximately 30% w / w to approximately 50% w / w.

[0329] (41) The pharmaceutical composition according to Embodiment 40, wherein the amount of microcrystalline cellulose is approximately 44% w / w to approximately 48% w / w.

[0330] (42) The pharmaceutical composition according to any one of Embodiments 34 to 41, wherein sodium starch glycolate is present in an amount of about 1% w / w to about 5% w / w.

[0331] (43) The pharmaceutical composition according to Embodiment 42, wherein the sodium starch glycolate is present in an amount of about 3% w / w to about 4% w / w.

[0332] (44) The pharmaceutical composition according to any one of Embodiments 34 to 43, wherein hydroxypropylcellulose LF is present in an amount of about 1% w / w to about 5% w / w.

[0333] (45) The pharmaceutical composition according to Embodiment 44, wherein hydroxypropylcellulose LF is present in an amount of about 2% w / w to about 3% w / w.

[0334] (46) The pharmaceutical composition according to any one of Embodiments 34 to 45, wherein the amount of colloidal silicon dioxide is about 0.5% w / w to about 5% w / w.

[0335] (47) The pharmaceutical composition according to Embodiment 46, wherein the amount of colloidal silicon dioxide is about 1% w / w to about 1.5% w / w.

[0336] (48) The pharmaceutical composition according to any one of Embodiments 34 to 47, wherein the magnesium stearate is present in an amount of about 0.5% w / w to about 5% w / w.

[0337] (49) The pharmaceutical composition according to Embodiment 48, wherein the magnesium stearate is present in an amount of about 1% w / w to about 1.5% w / w.

[0338] (50) A method for treating a disease or disorder in a subject requiring treatment, the method comprising the step of administering to the subject a therapeutically effective dose of a pharmaceutical composition according to any one of Embodiments 1 to 49.

[0339] (51) The method according to Embodiment 50, wherein the disease or disorder is an NLRP3-mediated disease or disorder.

[0340] (52) The method according to Embodiment 51, wherein the NLRP3-mediated disease or disorder is myelodysplastic syndrome, inflammatory disease or disorder, autoimmune disease or disorder, cardiovascular disease, neurodegenerative disease or disorder, bacterial and / or viral infection, allergy, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, erythrocytosis, graft rejection, lung injury, respiratory disease, ischemic condition, or a combination thereof.

[0341] (53) The method according to Embodiment 52, wherein the NLRP3-mediated disease or disorder is myelodysplastic syndrome or inflammatory disease or disorder.

[0342] (54) The method according to Embodiment 53, wherein the NLRP3-mediated disease or disorder is myelodysplastic syndrome.

[0343] (55) The method according to Embodiment 54, wherein the myelodysplastic syndrome is myelodysplastic syndrome with multiple systemic dysplasia, myelodysplastic syndrome with monosystemic dysplasia, myelodysplastic syndrome with ring sideroblasts, myelodysplastic syndrome with blast plasia, myelodysplastic syndrome with a single deletion, or an unclassifiable myelodysplastic syndrome.

[0344] (56) The method according to Embodiment 53, wherein the NLRP3-mediated disease or disorder is an inflammatory disease or disorder.

[0345] (57) The method according to embodiment 56, wherein the inflammatory disease or disorder is acute inflammatory pain.

[0346] (58) A method for treating myelodysplastic syndrome (MDS) in a subject requiring treatment for myelodysplastic syndrome (MDS), wherein the method involves applying formula (I) to the subject.

[0347] [ka] The process includes administering the compound, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. During the ceremony, A is C6~C 10 Aryl, C3~C 10 They are cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which has one or more R 6 Then, it is replaced by an optional selection. X is either CH or N. Y is NH, R 1 H is H, R 2 These are C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl, or 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. R 3 H is H, R 4These are heteroaryls selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, each of which is a halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkyl Optionally substituted with one or more substituents selected from nyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclyl, and C3-C8 halocycloalkyl. R 5 H is H, Each R 6 These are independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl, or C1-C6 haloalkyl. Here, (i) The subjects are those who have symptomatic anemia, (ii) The subjects are refractory, intolerant, or ineligible for treatment with erythropoiesis-stimulating agents (ESAs), and are selected on an optional basis, having discontinued previous ESA treatment at least two weeks prior to the administration step. (iii) The subjects have very low-risk MDS, low-risk MDS, or medium-risk MDS, (iv) The administration step involves orally administering the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to a subject. (v) The administration procedure involves administering the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to the subject once daily for 5 days, followed by a 2-day rest period, in a weekly regimen, which may optionally be carried out for approximately 4 to 56 weeks, or (vi) A method that is a combination of two or more of (i) to (v).

[0348] (59) A method for treating myelodysplastic syndrome (MDS) in a subject requiring treatment for myelodysplastic syndrome (MDS), the method comprising: administering epoetin alfa or darbepoetin alfa and formula (I)

[0349] [ka] The process includes administering the compound, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. During the ceremony, A is C6~C 10 Aryl, C3~C 10 They are cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which has one or more R 6 Then, it is replaced by an optional selection. X is either CH or N. Y is NH, R 1 H is H, R 2 These are C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl, or 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. R 3 H is H, R 4These are heteroaryls selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, each of which is a halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkyl Optionally substituted with one or more substituents selected from nyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclyl, and C3-C8 halocycloalkyl. R 5 H is H, Each R 6 A method in which the elements are independently a halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl, or C1-C6 haloalkyl.

[0350] (60) The method according to Embodiment 59, wherein, prior to the administration step, the subject has not responded to monotherapy treatment with the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0351] (61) The method according to Embodiment 59 or Embodiment 60, wherein epoetin α or darbepoetin α is administered every two weeks.

[0352] (62) The method according to any one of Embodiments 59 to 61, wherein a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to a subject in a regimen comprising administration once daily for 5 days for 28 days, followed by a 2-day period without administration.

[0353] (63) The method according to embodiment 62, wherein the 28-day cycle is carried out for approximately 1 to approximately 12 cycles.

[0354] (64) The method according to Embodiment 63, wherein at least eight 28-day cycles are performed, and epoetin alfa or darbepoetin alfa is administered between the fifth to eighth 28-day cycles.

[0355] (65) The method according to any one of embodiments 59 to 64, wherein epoetin α or darbepoetin α is administered subcutaneously.

[0356] (66) The method according to any one of embodiments 59 to 65, wherein the subject has symptomatic anemia.

[0357] (67) The method according to any one of embodiments 59 to 66, relating to a very low-risk MDS, a low-risk MDS, or a medium-risk MDS.

[0358] (68) The method according to any one of Embodiments 59 to 67, wherein the administration step comprises orally administering to a subject a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0359] (69) The method according to any one of Embodiments 58 to 68, wherein the dose of the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is approximately 1 mg to approximately 4 mg.

[0360] (70)R 2The method according to any one of embodiments 58 to 69, wherein is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl.

[0361] (71)R 2 teeth,

[0362] [ka] The pharmaceutical composition according to any one of embodiments 58 to 70.

[0363] (72)R 4 These are oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl, or 1,3,4-oxadiazolyl, each of which is a halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyano A pharmaceutical composition according to any one of embodiments 58 to 71, which is optionally substituted with one or more substituents selected from lucyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclylalkyl, and C3-C8 halocycloalkyl, as well as combinations thereof.

[0364] (73)R 4The pharmaceutical composition according to Embodiment 72, wherein is substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3-8 member heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclyl, or C3-C8 halocycloalkyl, or a combination thereof.

[0365] (74)R 4 The structure is as follows:

[0366] [ka] A pharmaceutical composition according to any one of embodiments 58 to 73, having one of the following.

[0367] (75)A is C6~C 10 Aryl, C3~C 10 Cycloalkyl or 5-6 membered monocyclic heteroaryl, each of which contains one or more R 6 The pharmaceutical composition according to any one of embodiments 58 to 74, which is optionally substituted.

[0368] (76) The pharmaceutical composition according to any one of Embodiments 58 to 69, wherein A is cyclohexyl, cyclohexenyl, phenyl, pyridinyl, or pyrimidinyl.

[0369] (77) The pharmaceutical composition according to Embodiment 76, wherein A is phenyl.

[0370] (78) The pharmaceutical composition according to any one of embodiments 58 to 77, wherein A is unsubstituted.

[0371] (79) A is one or more R 6 A pharmaceutical composition according to any one of embodiments 58 to 78, which is replaced by [the specified substance].

[0372] (80)R 6 The pharmaceutical composition according to Embodiment 79, wherein is chloro, fluoro, -CHF2, -CH2CH2OH, cyano, or methoxy.

[0373] (81) A is,

[0374] [ka] The pharmaceutical composition according to any one of embodiments 58 to 80.

[0375] (82) The compound is of formula (Ia)

[0376] [ka] A compound of, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, During the ceremony, R 2a This is a C3-C4 cycloalkyl that is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3-8 membered heterocyclyl. R 4a The pharmaceutical composition according to any one of embodiments 58 to 69, wherein is an isoxazolyl optionally substituted with one or more substituents selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, or C3-C8 haloalkylcycloalkyl.

[0377] (83)R 2a The pharmaceutical composition according to any one of embodiments 58 to 69, wherein is cyclopropyl.

[0378] (84)R 4a teeth,

[0379] [ka] The pharmaceutical composition according to any one of embodiments 58 to 69 or embodiment 83.

[0380] (85) The pharmaceutical composition according to any one of Embodiments 58 to 84, wherein the compound of formula (I) is listed in Table 1 or a pharmaceutically acceptable salt or solvate thereof.

[0381] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided merely as examples. Numerous variations, modifications, and substitutions will come to mind to those skilled in the art without departing from the present invention. It should be understood that various alternative forms of the embodiments of the present invention described herein may be employed when carrying out the present invention. The following claims define the scope of the present invention, and the methods and structures within these claims, as well as their equivalents, are intended to be encompassed thereby.

Claims

1. Equation (I) 【Chemistry 1】 A pharmaceutical composition comprising a compound thereof, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and at least one pharmaceutically acceptable excipient, During the ceremony, A is C ６ ~C １０ Ariel, C ３ ~C １０ They are cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which has one or more R ６ Then, it is replaced by an optional choice. X is CH or N, Y is NH, R １ H is, R ２ is C １ -C ６ alkyl, C ３ -C ４ cycloalkyl, C ３ -C ８ heterocyclyl, or 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, and 3-8 membered heterocyclyl R ３ H is, R ４ This is a heteroaryl selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, each of which is a halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Haloalkyl, C ３ ~C ８ Cycloalkyl, cyano, aminyl, C １ ~C ６ Hydroxylalkyl, C １ ~C ６ Cyanoalkyl, 3-8 membered heterocyclyl, C ３ ~C ８ Haloalkylcycloalkyl, C ３ ~C ８ Aminylalkylcycloalkyl, C ３ ~C ８ Alkylcycloalkyl, 3-8 member heterocyclylalkyl, 3-8 member alkylheterocyclylcycloalkyl, 3-8 member haloheterocyclylalkyl, and C ３ ~C ８ Optionally substituted with one or more substituents selected from halocycloalkyl groups, R ５ H is, Each R ６ They are independent, Hello, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, cyano, C １ ~C ６ Hydroxylalkyl, or C １ ~C ６ It is a haloalkyl, Herein, the amount of the compound of formula (I) in the pharmaceutical composition is about 0.5 to about 5 mg.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipient comprises sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, or magnesium stearate, or a combination of two or more thereof.

3. A method for treating an NLRP3-mediated disease or disorder in a subject requiring treatment for such a disease or disorder, the method comprising the step of administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 1 or claim 2.

4. The method according to claim 3, wherein the NLRP3-mediated disease or disorder is myelodysplastic syndrome.

5. The aforementioned compound is of formula (Ia) 【Chemistry 2】 A compound of, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, During the ceremony, R ２ａ However, halo, hydroxyl, cyano, aminyl, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ C is optionally substituted with one or more substituents selected from alkoxys and 3- to 8-membered heterocyclines. ３ ~C ４ It is a cycloalkyl, R ４ａ However, C １ ~C ６ Haloalkyl, C ３ ~C ８ Cycloalkyl, or C ３ ~C ８ The pharmaceutical composition according to claim 1 or claim 2, wherein the isoxazolyl is optionally substituted with one or more substituents selected from haloalkylcycloalkyl.

6. The pharmaceutical composition according to claim 1 or 2, wherein the compound of formula (I) is one of those listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

7. The compound of formula (I) is 【Chemistry 3-1】 【Chemistry 3-2】 The pharmaceutical composition according to claim 1 or claim 2, selected from a pharmaceutically acceptable salt or solvate thereof.

8. The pharmaceutical composition according to any one of claims 1 to 2 or 5 to 7, wherein the compound of formula (I) is compound 10 of Table 1.

9. The pharmaceutical composition according to any one of claims 1 to 2 or 5 to 8, wherein the amount of the compound of formula (I) in the pharmaceutical composition is about 4 mg.

10. The pharmaceutical composition according to any one of claims 1 to 2 or 5 to 8, wherein the amount of the compound of formula (I) in the pharmaceutical composition is about 5 mg.

11. The pharmaceutical composition according to any one of claims 1 to 2 or 5 to 8, wherein the amount of the compound of formula (I) in the pharmaceutical composition is about 2 mg.

12. The pharmaceutical composition according to any one of claims 1 to 2 or 5 to 8, wherein the amount of the compound of formula (I) in the pharmaceutical composition is about 0.5 mg.

13. The pharmaceutical composition according to any one of claims 1 to 2 or 5 to 12, wherein the pharmaceutical composition is a tablet.

14. The pharmaceutical composition according to claim 13, wherein the tablet is a film-coated immediate-release tablet.

15. The pharmaceutical composition according to claim 13 or 14, wherein the tablet is coated with Opadry II.

16. The pharmaceutical composition according to any one of claims 13 to 15, wherein the tablet has a diameter of about 7 mm.

17. The pharmaceutical composition according to any one of claims 1 or 5 to 16, wherein the pharmaceutically acceptable excipient comprises sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, magnesium stearate, or a combination of two or more thereof.

18. The pharmaceutical composition according to any one of claims 1 to 2 or 5 to 17, wherein the pharmaceutically acceptable excipient comprises at least three components selected from the group consisting of sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, and magnesium stearate.

19. The pharmaceutical composition according to any one of claims 1 to 2 or 5 to 18, wherein the pharmaceutically acceptable excipient comprises at least four components selected from the group consisting of sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, and magnesium stearate.

20. The pharmaceutical composition according to any one of claims 1 to 2 or 5 to 19, wherein the pharmaceutically acceptable excipient comprises at least five components selected from the group consisting of sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, and magnesium stearate.

21. The pharmaceutical composition according to any one of claims 1 to 2 or 5 to 20, wherein the pharmaceutically acceptable excipient comprises sodium lauryl sulfate, partially gelatinized corn starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose LF, colloidal silicon dioxide, and magnesium stearate.

22. The pharmaceutical composition according to claim 2 or any one of claims 17 to 21, wherein the amount of sodium lauryl sulfate is about 0.01% w / w to about 0.1% w / w.

23. The pharmaceutical composition according to claim 2 or any one of claims 17 to 22, wherein the partially gelatinized corn starch is present in an amount of about 30% w / w to about 50% w / w.

24. The pharmaceutical composition according to claim 2 or any one of claims 17 to 23, wherein the amount of microcrystalline cellulose is about 30% w / w to about 50% w / w.

25. The pharmaceutical composition according to claim 2 or any one of claims 17 to 24, wherein the sodium starch glycolate is present in an amount of about 1% w / w to about 5% w / w.

26. The pharmaceutical composition according to claim 2 or any one of claims 17 to 25, wherein the hydroxypropylcellulose LF is present in an amount of about 1% w / w to about 5% w / w.

27. The pharmaceutical composition according to claim 2 or any one of claims 17 to 26, wherein the colloidal silicon dioxide is present in an amount of about 0.5% w / w to about 5% w / w.

28. The pharmaceutical composition according to claim 2 or any one of claims 17 to 27, wherein the magnesium stearate is present in an amount of about 0.5% w / w to about 5% w / w.

29. The pharmaceutical composition according to claim 21, wherein the amount of sodium lauryl sulfate is about 0.01% w / w to about 0.1% w / w, the amount of partially gelatinized corn starch is about 43% w / w to about 44% w / w, the amount of microcrystalline cellulose is about 44% w / w to about 48% w / w, the amount of sodium starch glycolate is about 3% w / w to about 4% w / w, the amount of hydroxypropyl cellulose LF is about 2% w / w to about 3% w / w, the amount of colloidal silicon dioxide is about 1% w / w to about 1.5% w / w, and the amount of magnesium stearate is about 1% w / w to about 1.5% w / w.

30. The pharmaceutical composition according to any one of claims 1 to 2 or 5 to 29, wherein the sodium lauryl sulfate is Kolliphore SLS fine, the partially gelatinized corn starch is Starch 1500, the microcrystalline cellulose is Avicel PH 101, the sodium starch glycolate is type A, the hydroxypropyl cellulose LF is Klucel HPC LF, and the colloidal silicon dioxide is Aerosil Pharma 200.

31. A method for treating an NLRP3-mediated disease or disorder in a subject requiring treatment for the NLRP3-mediated disease or disorder, the method comprising the step of administering to the subject a therapeutically effective dose of the pharmaceutical composition described in any one of claims 1 to 2 or 5 to 30.

32. The method according to claim 31, wherein the NLRP3-mediated disease or disorder is myelodysplastic syndrome, inflammatory disease or disorder, autoimmune disease or disorder, cardiovascular disease, neurodegenerative disease or disorder, bacterial and / or viral infection, allergy, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, anemia, graft rejection, lung injury, respiratory disease, ischemic condition, or a combination thereof.

33. The method according to claim 31, wherein the NLRP3-mediated disease or disorder is myelodysplastic syndrome or an inflammatory disease or disorder.

34. The method according to claim 33, wherein the NLRP3-mediated disease or disorder is myelodysplastic syndrome.

35. The method according to claim 34, wherein the myelodysplastic syndrome is myelodysplastic syndrome with multiple systemic dysplasia, myelodysplastic syndrome with monosystemic dysplasia, myelodysplastic syndrome with ring sideroblasts, myelodysplastic syndrome with blast elimination, myelodysplastic syndrome with a single deletion, or an unclassifiable myelodysplastic syndrome.

36. The method according to claim 33, wherein the NLRP3-mediated disease or disorder is an inflammatory disease or disorder.

37. The method according to claim 36, wherein the inflammatory disease or disorder is acute inflammatory pain.

38. The method according to any one of claims 31 to 37, wherein the pharmaceutical composition is administered daily.

39. The method according to any one of claims 31 to 38, wherein the pharmaceutical composition is administered daily for about one week to about twelve weeks.

40. The method according to any one of claims 31 to 38, wherein the pharmaceutical composition is administered daily for about 12 weeks or more.

41. A method for treating myelodysplastic syndrome (MDS) in a subject requiring treatment for myelodysplastic syndrome (MDS), wherein the method involves applying formula (I) to the subject. 【Chemistry 4】 The process includes administering the compound, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. During the ceremony, A is C ６ ~C １０ Ariel, C ３ ~C １０ They are cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which has one or more R ６ Then, it is replaced by an optional choice. X is CH or N, Y is NH, R １ H is, R ２ is C １ to C ６ alkyl, C ３ to C ４ cycloalkyl, C ３ to C ８ heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one further substituent selected from halo, hydroxyl, cyano, aminyl, C １ to C ６ alkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, C １ to C ６ alkoxy, and 3- to 8-membered heterocyclyl, and is optionally substituted R ３ H is, R ４ is heteroaryl selected from oxazolyl, isoxazolyl, 1,2,3 - oxadiazolyl, 1,2,4 - oxadiazolyl, 1,2,5 - oxadiazolyl, 1,3,4 - oxadiazolyl, 1,2,3 - triazolyl, 1,2,4 - triazolyl, thiazolyl, isothiazolyl, 1,2,3 - thiadiazolyl, 1,2,4 - thiadiazolyl, 1,2,5 - thiadiazolyl, and 1,3,4 - thiadiazolyl, each of which is halo, C １ ~C ６ alkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ alkynyl, C １ ~C<00,00104>haloalkyl, C ３ ~C<00001,06>cycloalkyl, cyano, aminyl, C<00,00107>~C ６ hydroxyalkyl, C １ ~C ６ cyanoalkyl, 3 - to 8 - member heterocyclyl, C ３ ~C ８ haloalkylcycloalkyl, C ３ ~C ８ aminylalkylcycloalkyl, C ３ ~C ８ alkylcycloalkyl, 3 - to 8 - member heterocyclylalkyl, 3 - to 8 - member alkylheterocyclylcycloalkyl, 3 - to'8 - member haloheterocyclylalkyl, and C ３ ~C ８ halocycloalkyl, and R ５ H is, Each R ６ They are independent, Hello, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, cyano, C １ ~C ６ Hydroxylalkyl, or C １ ~C ６ It is a haloalkyl, Here, (i) The subject has symptomatic anemia, (ii) The subject is refractory, intolerant, or unsuitable for treatment with an erythropoiesis-stimulating agent (ESA), and optionally, the subject has discontinued the previous ESA at least two weeks prior to the administration step. (iii) The subject has a very low-risk MDS, a low-risk MDS, or a medium-risk MDS, (iv) The administration step includes orally administering the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to the subject. (v) The administration step includes administering the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to the subject on a daily basis, or (vi) A method that is a combination of two or more of (i) to (v).

42. The method according to claim 41, wherein the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject on a daily basis.

43. The method according to claim 41 or claim 42, wherein the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject daily for about one week to about twelve weeks.

44. The method according to claim 41 or claim 42, wherein the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject daily for 12 weeks or more.

45. The method according to any one of claims 41 to 44, wherein the administration step comprises orally administering the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to the subject.

46. The method according to any one of claims 41 to 45, wherein the amount of the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is about 0.5 mg to about 5 mg.

47. The compound of formula (I) is of formula (Ia) 【Transformation 5】 A compound of, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, During the ceremony, R ２ａ However, halo, hydroxyl, cyano, aminyl, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ C is optionally substituted with one or more substituents selected from alkoxys and 3- to 8-membered heterocyclines. ３ ~C ４ It is a cycloalkyl, R ４ａ However, C １ ~C ６ Haloalkyl, C ３ ~C ８ Cycloalkyl, or C ３ ~C ８ The method according to any one of claims 41 to 46, wherein the isoxazolyl is optionally substituted with one or more substituents selected from haloalkylcycloalkyl.

48. The method according to any one of claims 41 to 47, wherein the compound of formula (I) is one of those listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

49. The method according to any one of claims 41 to 47, wherein the compound of formula (I) is compound 10 of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

50. The compound of formula (I) is 【Chemistry 6-1】 【Chemistry 6-2】 The method according to any one of claims 41 to 46, or selected from a pharmaceutically acceptable salt or solvate thereof.

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